Fused heterocyclic compounds

ABSTRACT

There is provided a CRF receptor antagonist comprising a compound of the formula (I): 
                         
wherein R 1  is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group, a cyano or an acyl; R 2  is an optionally substituted cyclic hydrocarbyl or an optionally substituted heterocyclic group; X is oxygen, sulfur or —NR 3 — (wherein R 3  is a hydrogen, an optionally substituted hydrocarbyl or an acyl); Y 1 , Y 2  and Y 3  are each an optionally substituted carbon or a nitrogen, provided that one or less of Y 1 , Y 2  and Y 3  is nitrogen; and Z is a bond, —CO—, oxygen, sulfur, —SO—, —SO 2 —, —NR 4 —, —NR 4 -alk-, —CONR 4 — or —NR 4 CO— (wherein alk is an optionally substituted C 1-4  alkylene and R 4  is a hydrogen, an optionally substituted hydrocarbyl or an acyl); or a salt thereof or a prodrug thereof.

This application is a U.S. national stage of International ApplicationNo. PCT/US2006/015646 filed Apr. 26, 2006 which claims the benefit ofU.S. Provisional Application No 60/675,113, filed Apr. 27, 2005 andclaims the benefit of U.S. Provisional Application No. 60/742,101, filedDec. 2, 2005.

TECHNICAL FIELD

The present invention relates to novel nitrogen-containing fusedheterocyclic compounds having CRF (corticotropin releasing factor)antagonistic activity and pharmaceutical compositions containing them.

BACKGROUND ART

Corticotropin-releasing factor (hereinafter, abbreviated as “CRF”) is aneuropeptide composed of 41 amino acids, and was isolated and purifiedas a peptide promoting release of adrenocorticotropic hormone (ACTH)from pituitary gland. First, the structure thereof was determined fromsheep hypothalamus and, thereafter, the presence thereof was confirmedalso in a rat or a human, and the structure thereof was determined[Science, 213, 1394 (1981); Proc. Natl. Acad. Sci. USA, 80, 4851 (1983);EMBO J. 5, 775 (1983)]. An amino acid sequence is the same in a humanand a rat, but differed in 7 amino acids in ovine. CRF is synthesized asa carboxy-terminal of prepro CRF, cut and secreted. The CRF peptide anda mRNA thereof are present at the largest amount in hypothalamus andpituitary gland, and are widely distributed in a brain such as cerebralcortex, cerebellum, hippocampus and corpus amygdaloideum. In addition,in peripheral tissues, the existence has been confirmed in placenta,adrenal gland, lung, liver, pancreas, skin and digestive tract [J. Clin.Endocrinol. Metab., 65, 176 (1987); J. Clin. Endocrinol. Metab., 67, 768(1988); Regul. Pept., 18, 173 (1987), Peptides, 5 (Suppl. 1), 71(1984)]. A CRF receptor is a 7-transmembrane G protein-coupled receptor,and two subtypes of CRF1 and CRF2 are present. It is reported that CRF1is present mainly in cerebral cortex, cerebellum, olfactory bulb,pituitary gland and tonsil nucleus. On the other hand, the CRF2 receptorhas two subtypes of CRF2α and CRF2β. It was made clear that the CRF2αreceptor is distributed much in hypothalamus, septal area and choroidsplexus, and the CRF2β receptor is present mainly in peripheral tissuessuch as skeletal muscle and is distributed in a blood vessel in a brain[J. Neurosci. 15, 6340 (1995); Endocrinology, 137, 72 (1996); Biochim.Biophys. Acta, 1352, 129 (1997)]. Since each receptor differs indistribution in a living body, it is suggested that a role thereof isalso different [Trends. Pharmacol. Sci. 23, 71 (2002)].

As a physiological action of CRF, the action on the endocrine system isknown in which CRF is produced and secreted in response to stress inhypothalamus and acts on pituitary gland to promote the release of ACTH[Recent Prog. Horm. Res., 39, 245 (1983)]. In addition to the action onthe endocrine system, CRF acts as a neurotransmitter or aneuroregulating factor in a brain, and integrates electrophysiology,autonomic nerve and conducts to stress [Brain Res. Rev., 15, 71 (1990);Pharmacol. Rev., 43, 425 (1991)]. When CRF is administered in a cerebralventricle of experimental animal such as a rat, anxiety conduct isobserved, and much more anxiety conduct is observed in aCRF-overexpressing mouse as compared with a normal animal [Brain Res.,574, 70 (1992); J. Neurosci., 10, 176 (1992); J. Neurosci., 14, 2579(1994)]. In addition, α-helical CRF(9-41) of a peptidergic CRF receptorantagonist exerts an anti-anxiety action in an animal model [Brain Res.,509, 80 (1990); J. Neurosci., 14, 2579 (1994)]. A blood pressure, aheart rate and a body temperature of a rat are increased by stress orCRF administration, but the α-helical CRF(9-41) of a peptidergic CRFantagonist inhibits the increase in a blood pressure, a heart rate and abody temperature due to stress [J. Physiol., 460, 221 (1993)]. Theα-helical CRF(9-41) of a peptidergic CRF receptor antagonist inhibitsabnormal conducts due to withdrawal of a dependent drug such as analcohol and a cocaine [Psychopharmacology, 103, 227 (1991); Pharmacol.Rev. 53, 209 (2001)]. In addition, it has been reported that learningand memory are promoted by CRF administration in a rat [Nature, 375, 284(1995); Neuroendocrinology, 57, 1071 (1993); Eur. J. Pharmacol., 405,225 (2000)].

Since CRF is associated with stress response in a living body, there areclinical reports regarding stress-associated depression or anxiety. TheCRF concentration in a cerebrospinal fluid of a depression patient ishigher as compared with that of a normal person [Am. J. Psychiatry, 144,873 (1987)], and the mRNA level of CRF in hypothalamus of a depressionpatient is increased as compared with that of a normal person [Am. J.Psychiatry, 152, 1372 (1995)]. A CRF binding site of cerebral cortex ofa patient who suicided by depression is decreased [Arch. Gen.Psychiatry, 45, 577 (1988)]. The increase in the plasma ACTHconcentration due to CRF administration is small in a depression patient[N. Engl. J. Med., 314, 1329 (1986)]. In a patient with panic disorder,the increase of plasma ACTH concentration due to CRF administration issmall [Am. J. Psychiatry, 143, 896 (1986)]. The CRF concentration in acerebrospinal fluid of a patient with anxiety induced by stress such asobsessive-compulsive neurosis, post-psychic trauma stress disorder,Tourette's syndrome and the like is higher as compared with that of anormal person [Arch. Gen. Psychiatry, 51, 794 (1994); Am. J. Psychiatry,154, 624 (1997); Biol. Psychiatry, 39, 776 (1996)]. The CRFconcentration in a cerebrospinal fluid of schizophrenics is higher ascompared with that of a normal person [Brain Res., 437, 355 (1987);Neurology, 37, 905 (1987)]. Thus, it has been reported that there isabnormality in the living body response system via CRF instress-associated mental disease.

The action of CRF on the endocrine system can be presumed by thecharacteristics of CRF gene-introduced animal and actions in anexperimental animal. In a CRF-overexpressing mouse, excessive secretionsof ACTH and adrenal cortex steroid occur, and abnormalities analogous toCushing's syndrome such as atrophy of muscle, alopecia, infertility andthe like are observed [Endocrinology, 130, 3378 (1992)]. CRF inhibitsingestion in an experimental animal such as a rat [Life Sci., 31, 363(1982); Neuropharmacology, 22, 337 (1983)]. In addition, α-helicalCRF(9-41) of a peptidergic CRF antagonist inhibited decrease ofingestion due to stress loading in an experimental model [Brain Res.Bull., 17, 285 (1986)]. CRF inhibited weight gain in a hereditaryobesity animal [Physiol. Behav., 45, 565 (1989)]. In a nervous orexiainactivity patient, the increase of ACTH in plasma upon CRFadministration is small [J. Clin. Endocrinol. Metab., 62, 319 (1986)].It has been suggested that a low CRF value is associated with obesitysyndrome [Endocrinology, 130, 1931 (1992)]. There has been suggested apossibility that ingestion inhibition and weight loss action of aserotonin reuptake inhibiting agent are exerted via release of CRF[Pharmacol. Rev., 43, 425 (1991)].

CRF is centrally or peripherally associated with the digestive tractmovement involved in stress or inflammation [Am. J. Physiol.Gastrointest. Liver Physiol. 280, G315 (2001)]. CRF acts centrally orperipherally, weakens the shrinkablity of stomach, and decreases thegastric excreting ability [Regulatory Peptides, 21, 173 (1988); Am. J.Physiol., 253, G241 (1987)]. In addition, α-helical CRF (9-41) of apeptidergic CRF antagonist has a restoring action for hypofunction ofstomach by abdominal operation [Am. J. Physiol., 258, G152 (1990)]. CRFinhibits secretion of a bicarbonate ion in stomach, decreases gastricacid secretion and inhibits ulcer due to cold restriction stress [Am. J.Physiol., 258, G152 (1990)]. Furthermore, α-helical CRF (9-41) of apeptidergic CRF antagonist shows the inhibitory action on gastric acidsecretion decrease, gastric excretion decrease, small intestinaltransport decrease and large intestinal transport enhancement due torestriction stress [Gastroenterology, 95, 1510 (1988)]. In a healthyperson, mental stress increases a gas and abdominal pain due to anxietyand intestine dilation, and CRF decreases a threshold of discomfort[Gastroenterology, 109, 1772 (1995); Neurogastroenterol. Mot., 8, 9[1996]. In a irritable bowel syndrome patient, large intestinal movementis excessively enhanced by CRF administration as compared with a healthyperson [Gut, 42, 845 (1998)].

It has been reported from studies on experimental animals and clinicalstudies that CRF is induced by inflammation and is involved in ainflammatory reaction. In an inflammatory site of an experimental animaland in a joint fluid of a rheumatoid arthritis patient, production ofCRF is topically increased [Science, 254, 421 (1991); J. Clin. Invest.,90, 2555 (1992); J. Immunol., 151, 1587 (1993)]. CRF inducesdegranulation of a mast cell and enhances the blood vessel permeability[Endocrinology, 139, 403 (1998); J. Pharmacol. Exp. Ther., 288, 1349(1999)]. CRF can be detected also in a thyroid gland of autoimmunethyroiditis patient [Am. J. Pathol. 145, 1159 (1994)]. When CRF isadministered to an experimental autoimmune cerebrospinal meningitis rat,the progression of symptom such as paralysis was remarkably inhibited[J. Immunil., 158, 5751 (1997)]. In a rat, the immune response activitysuch as T-lymphocyte proliferation and the natural killer cell activityis reduced by CRF administration or stress loading [Endocrinology, 128,1329 (1991)].

From the above-mentioned reports, it is expected that the CRF receptorantagonistic compound would exert an excellent effect for treating orpreventing various diseases in which CRF is involved.

As a CRF antagonist, for example, peptide CRF receptor antagonists arereported in which a part of an amino acid sequence of CRF or associatedpeptides of a human or other mammals is altered or deleted, and they arereported to show a pharmacological action such as ACTHrelease-inhibiting action and anti-anxiety action [Science, 224, 889(1984); J. Pharmacol. Exp. Ther., 269, 564 (1994); Brain Res. Rev., 15,71 (1990)]. However, from a pharmacokinetic point of view such aschemical stability and absorbability for oral administration in a livingbody, bioavailability and intracerebral transferability, peptidederivatives have a low utility value as a medicine.

DISCLOSURE OF INVENTION

According to the present invention, there is provided:

(1) A compound represented by the formula (I):

wherein R¹ is an optionally substituted hydrocarbyl, an optionallysubstituted C-linked heterocyclic group, an optionally substitutedN-linked heteroaryl group, or an acyl, provided that methyl, andtrifluoromethyl are excluded;R² is an optionally substituted cyclic hydrocarbyl or an optionallysubstituted heterocyclic group, provided that2-[2-(1,1-dimethylethyl)phenyloxy]-3-pyridinyl is excluded;X is oxygen, sulfur or —NR³— (wherein R³ is a hydrogen, an optionallysubstituted hydrocarbyl or an acyl);Y¹, Y² and Y³ are each an optionally substituted carbon or a nitrogen,provided that one or less of Y¹, Y² and Y³ is nitrogen; andZ is a bond, —CO—, oxygen, sulfur, —SO—, —SO₂—, —NR⁴—, —NR⁴-alk-,—CONR⁴— or —NR⁴CO— (wherein alk is an optionally substituted C₁₋₄alkylene and R⁴ is a hydrogen, an optionally substituted hydrocarbyl oran acyl);provided that

-   (i) the compound wherein X is —NH—, and R² is an optionally    substituted thiophene ring,-   (ii) the compound wherein R¹ is cyano, Y³ is carbon which is    substituted with methyl substituted with three substituents, one of    which is acyl, and other two of which may form a ring,-   (iii) a)    6-amino-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazole-7-carbonitrile,-   b)    6-amino-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazole-7-carboxamide,    and-   c)    6-{[(allylamino)carbonothioyl]amino}-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazole-7-carboxamide,-   (iv)    4-({2-[(4-chlorophenyl)amino]-1,7-dimethyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide,-   (v) the compound wherein R³ is substituted heteroarylmethyl, R² is    4-piperidinyl bearing a substituent at the 1-position,-   (vi) the compound wherein R² is substituted    8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-7-yl, and-   (vii)    7-ethyl-1-methyl-N-[4-(trifluoromethoxy)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-amine    and    7-ethenyl-1-methyl-N-[4-(trifluoromethoxy)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-amine    are excluded; or a salt thereof;    (2) A prodrug of the compound according to the above-mentioned (1);    (3) The compound according to the above-mentioned (1) wherein R¹ is    an optionally substituted acyclic branched C₃₋₁₁ hydrocarbyl;    (4) The compound according to the above-mentioned (1) wherein R¹ is    an optionally substituted C₆₋₁₀ aryl;    (5) The compound according to the above-mentioned (1) wherein R¹ is    an optionally substituted C-linked 5- to 14-membered heterocyclic    group or N-linked 5- to 10-membered heteroaryl group;    (6) The compound according to the above-mentioned (1) wherein X is    —NR³— (wherein R³ is as defined in the above-mentioned (1));    (7) The compound according to the above-mentioned (6) wherein R³ is    methyl, ethyl or hydroxyethyl;    (8) The compound according to the above-mentioned (1) wherein Y¹ is    CR^(3a), Y² is CR^(3b), and Y³ is CR^(3c) (wherein R^(3a), R^(3b)    and R^(3c) are independently a hydrogen, a halogen, a nitro, a    cyano, an optionally substituted C₁₋₄ hydrocarbyl, an optionally    substituted C₁₋₄ hydrocarbyloxy, an optionally substituted C₁₋₄    hydrocarbylthio, an optionally substituted amino or an acyl    containing up to 4 carbon atoms;    (9) The compound according to the above-mentioned (8) wherein R^(3a)    is a hydrogen, a halogen, a cyano, an optionally substituted C₁₋₃    alkyl, or an optionally substituted C₁₋₃ alkoxy, R^(3b) is a    hydrogen, and R^(3c) is a hydrogen;    (10) The compound according to the above-mentioned (9) wherein    R^(3a) is chlorine, bromine, methoxy or methyl;    (11) The compound according to the above-mentioned (1) wherein one    of Y¹, Y² and Y³ is nitrogen;    (12) The compound according to the above-mentioned (1) wherein R² is    an optionally substituted C₆₋₁₀ aryl or an optionally substituted 5-    to 8-membered heterocyclic group;    (13) The compound according to the above-mentioned (1) wherein R² is    phenyl which is 2,4,6-trisubstituted, 2,4,5-trisubstituted or    2,4-disubstituted;    (14) The compound according to the above-mentioned (1) wherein Z is    —NR⁴— (wherein R⁴ is as defined in the above-mentioned (1)), or    oxygen;    (15) The compound according to the above-mentioned (14) wherein R⁴    is a hydrogen;    (16) The compound according to the above-mentioned (1) which is-   N-(4-chloro-2-methoxy-6-methylphenyl)-7-(2-ethylphenyl)-1-methyl-1H-benzimidazol-2-amine,-   N-(4-bromo-2-methoxy-6-methylphenyl)-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazol-2-amine,-   N-(4-bromo-2-methoxy-6-methylphenyl)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine,-   4-chloro-2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole,-   N-(4-chloro-2-methoxy-6-methylphenyl)-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazol-2-amine,    or-   2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole,    or a salt thereof;    (17) A process for producing the compound according to the    above-mentioned (1), which comprises reacting a compound represented    by the formula:

wherein L represents a leaving group selected from halogen atom,sulfonyloxy group and acyloxy group, and other symbols are as defined inthe above-mentioned (1), with a compound represented by the formula:R²—ZH  (ii)wherein each symbol is as defined in the above-mentioned (1);(18) A pharmaceutical composition which comprises the compound accordingto the above-mentioned (1);(19) A CRF receptor antagonist which is the compound represented by theformula (I′):

wherein R¹ is an optionally substituted hydrocarbyl, an optionallysubstituted C-linked heterocyclic group, an optionally substitutedN-linked heteroaryl group, a cyano or an acyl;R² is an optionally substituted cyclic hydrocarbyl or an optionallysubstituted heterocyclic group;X is oxygen, sulfur or —NR³— (wherein R³ is a hydrogen, an optionallysubstituted hydrocarbyl or an acyl);Y¹, Y² and Y³ are each an optionally substituted carbon or a nitrogen,provided that one or less of Y¹, Y² and Y³ is nitrogen;Z is a bond, —CO—, oxygen, sulfur, —SO—, —SO₂—, —NR⁴—, NR⁴-alk-, —CONR⁴—or —NR⁴CO— (wherein alk is an optionally substituted C₁₋₄ alkylene andR⁴ is a hydrogen, an optionally substituted hydrocarbyl or an acyl); ora salt thereof;(20) A method for treating or preventing a disease wherein a CRFreceptor is implicated, which comprises administering to a subject inneed thereof an effective amount of the CRF receptor antagonistaccording to the above-mentioned (19);(21) The method according to the above-mentioned (20) wherein thedisease being treated or prevented is selected from affective disorder,depression or anxiety;(22) Use of the CRE receptor antagonist according to the above-mentioned(19) for manufacturing a medicament for preventing or treating a diseasewherein a CRF receptor is implicated;(23) The use according to the above-mentioned (22) wherein the diseasebeing treated or prevented is selected from affective disorder,depression or anxiety;(24) A pharmaceutical composition for preventing or treating a diseasewherein a CRF receptor is implicated, which comprises the CRF receptorantagonist according to the above-mentioned (19);(25) The pharmaceutical composition according to the above-mentioned(24) wherein the disease being treated or prevented is selected fromaffective disorder, depression or anxiety; and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present specification, the term “hydrocarbyl” means a univalentgroup containing only carbon and hydrogen.

In the formula (I) and (I′), X represents an oxygen, a sulfur or —NR³—(wherein R³ is a hydrogen, an optionally substituted hydrocarbyl or anacyl). That is, examples of the 5-membered ring in the formula (I) and(I′) include an oxazole ring, a thiazole ring and an imidazole ring.

Examples of the “hydrocarbyl” of the “optionally substitutedhydrocarbyl” represented by R³ of the formula: —NR³— include anoptionally substituted aliphatic hydrocarbon group, an optionallysubstituted alicyclic hydrocarbon group, an optionally substitutedalicyclic-aliphatic hydrocarbon group, an optionally substitutedalicyclic-alicyclic hydrocarbon group, an optionally substitutedaromatic hydrocarbon group, an optionally substituted aromatic-aliphatichydrocarbon group (an aralkyl group), and the like.

Examples of said aliphatic hydrocarbon group include a saturatedaliphatic hydrocarbon group having 1-8 carbon atoms (e.g., alkyl group)such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl,heptyl, octyl, etc.; and an unsaturated aliphatic hydrocarbon grouphaving 2-8 carbon atoms (e.g., alkenyl group, alkynyl group, alkadienylgroup, alkadiynyl group, etc.) such as vinyl, allyl, 1-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 2,4-hexadienyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl, 2,4-hexadiynyl, 1-heptynyl, 1-octynyl, etc.

Examples of said alicyclic hydrocarbon group include a saturatedalicyclic hydrocarbon group having 3-7 carbon atoms (e.g., cycloalkylgroup, etc.) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and the like; an unsaturated alicyclic hydrocarbon grouphaving 3-7 carbon atoms (e.g., cycloalkenyl group, cycloalkadienylgroup, etc.) such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl,1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl,2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl, etc.; a partlysaturated and fused bicyclic hydrocarbon group [preferably, C₉₋₁₀ partlysaturated and fused bicyclic hydrocarbon group, etc. (including thosewhere the benzene ring is combined to 5- or 6-membered non-aromaticcyclic hydrocarbon group)] such as 1-indenyl, 2-indenyl, 1-indanyl,2-indanyl, 1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl,1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-naphthyl,1,4-dihydro-2-naphthyl, 3,4-dihydro-1-naphthyl, 3,4-dihydro-2-naphthyl,etc.; and the like. Said alicyclic hydrocarbon group may becross-linked.

Examples of said alicyclic-aliphatic hydrocarbon group include thosewhere the above-mentioned alicyclic hydrocarbon group and theabove-mentioned aliphatic hydrocarbon group are combined, for example,those having 4-14 carbon atoms such as cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl,2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclopentylethyl,cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl,cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl,2-(3,4-dihydro-2-naphtyl)ethyl, 2-(1,2,3,4-tetrahydro-2-naphtyl)ethyl,2-(3,4-dihydro-2-naphtyl)ethenyl, etc. (e.g., C₃₋₇ cycloalkyl-C₁₋₄ alkylgroup, C₃₋₇ cycloalkenyl-C₁₋₄ alkyl group, C₃₋₇ cycloalkyl-C₂₋₄ alkenylgroup, C₃₋₇ cycloalkenyl-C₂₋₄ alkenyl group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon-C₁₋₄ alkyl group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon-C₂₋₄ alkenyl groups, etc.).

Examples of said alicyclic-alicyclic hydrocarbon group include a C₁₋₄alkyl group substituted with two C₃₋₇ cycloalkyls selected from theabove-mentioned alicyclic hydrocarbon group, for example, thoserepresented by the formula:

Examples of said aromatic hydrocarbon group include an aryl group having6-10 carbon atoms (including that where a 5- to 6-membered non-aromatichydrocarbon ring is fused with phenyl group) such as phenyl, α-naphthyl,β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl,5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl,5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl,5,6-dihydro-4-naphthyl, etc.; and the like.

Examples of said aromatic-aliphatic hydrocarbon group include an aralkylgroup having 7-14 carbon atoms (C₆₋₁₀ aryl-C₁₋₄ alkyl group) such asphenyl-C₁₋₄ alkyl group, e.g., benzyl, phenethyl, 1-phenylethyl,1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, etc.; naphthyl-C₁₋₄alkyl group such as α-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl,β-naphthylethyl, etc.; C₆₋₁₀ aryl-C₂₋₄ alkenyl group such as phenyl-C₂₋₄alkenyl group, e.g., styryl, cinnamyl, etc.; and the like.

The above-mentioned “hydrocarbyl” group may have a substituent at asubstitutable position. Examples of such substituent include a halogen,nitro, cyano, oxo, (1) an optionally substituted heterocyclic group, (2)an optionally substituted sulfinyl group, (3) an optionally substitutedsulfonyl group, (4) optionally substituted hydroxyl group, (5)optionally substituted thiol group, (6) an optionally substituted aminogroup, (7) an acyl group, (8) an optionally esterified or amidatedcarboxyl group, (9) an optionally substituted phosphoryl group, or thelike.

Examples of the substituent of above-mentioned (2) an optionallysubstituted sulfinyl group, (3) an optionally substituted sulfonylgroup, (4) optionally substituted hydroxyl group, (5) optionallysubstituted thiol group and (6) an optionally substituted amino groupinclude an optionally substituted hydrocarbyl. Examples of “hydrocarbyl”of such optionally substituted hydrocarbyl include those exemplifiedabove. Such hydrocarbyl may be substituted by one or more substituentsat a substitutable position. Examples of the substituent group of theoptionally substituted hydrocarbyl as a substituent group includehalogen, nitro, cyano, hydroxyl, thiol, amino and carboxyl.

As the optionally substituted sulfinyl group of above-mentioned (2),specifically, C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl,propylsulfinyl, butylsulfinyl etc.) and C₆₋₁₀ arylsulfinyl (e.g.,phenylsulfinyl, naphthylsulfinyl etc.) are exemplified.

As the optionally substituted sulfonyl group of above-mentioned (3),specifically, C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl,propylsulfonyl, butylsulfonyl etc.) and C₆₋₁₀ arylsulfonyl (e.g.,phenylsulfonyl, naphthylsulfonyl etc.) are exemplified.

As the optionally substituted hydroxyl group of above-mentioned (4),specifically, hydroxyl, C₁₋₆ alkoxy (e.g., methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy,isopentyloxy, neopentyloxy, etc.) and C₆₋₁₀ aryloxy (e.g., phenoxy,naphthoxy, etc.) are exemplified.

As the optionally substituted thiol group of above-mentioned (5),specifically, thiol, C₁₋₆ alkylthio (e.g., methylthio, ethylthio,propylthio, etc.) and C₆₋₁₀ arylthio (e.g., phenylthio, naphthylthioetc.) are exemplified.

As the optionally substituted amino group of above-mentioned (6),specifically, amino, mono-C₁₋₆ alkylamino (e.g., methylamino,ethylamino, propylamino, isopropylamino, butylamino etc.), di-C₁₋₆alkylamino (e.g., dimethylamino, diethylamino, ethylmethylamino,dipropylamino, diisopropylamino, dibutylamino etc.), and the like areexemplified.

Examples of the acyl group of above-mentioned (7) include the same groupas the acyl for R³.

Examples of the ester group or amide group of the optionally esterifiedor amidated carboxyl group of above-mentioned (8) include ester groupwith the same optionally substituted hydrocarbyl as the substituent ofoptionally substituted hydroxyl group of above-mentioned (4) or amidegroup with optionally substituted amino group of above-mentioned (6).

As the optionally esterified carboxyl group, specifically, carboxyl,C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl etc.), C₆₋₁₀ aryloxy-carbonyl(e.g., phenoxycarbonyl etc.), C₇₋₁₆ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, phenethyloxycarbonyl etc.), and the like areexemplified.

As the optionally amidated carboxyl group, specifically, carbamoyl,mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.),di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl etc.), C₆₋₁₀ aryl-carbamoyl (e.g., phenylcarbamoyl,1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), 5- to 6-memberedheterocyclic carbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl,4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl etc.), andthe like are exemplified.

Examples of the “acyl” represented by R³ of the formula: —NR³— include aformyl and a group where the carbonyl group is combined with a C₁₋₁₀alkyl group, a C₂₋₁₀ alkenyl group, a C₂₋₁₀ alkynyl group, a C₃₋₇cycloalkyl group, a C₅₋₇ cycloalkenyl group or an aromatic group (e.g.,phenyl group, pyridyl group, etc.) (e.g., acetyl, propionyl, butyryl,isobytyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl,cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl,2-cyclohexenecarbonyl, benzoyl, etc.) and the like.

R³ is preferably hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,and more preferably hydrogen, C₁₋₁₀ alkyl.

Specifically, as R³, methyl, ethyl, hydroxyethyl and the like arepreferred.

R¹ in the formula (I) and (I′) is an optionally substituted hydrocarbyl,an optionally substituted C-linked heterocyclic group, an optionallysubstituted N-linked heteroaryl group, a cyano or an acyl. Here, theterm “C-linked” of said “optionally substituted C-linked heterocyclicgroup” means that R¹ is linked via a carbon atom of the heterocyclicgroup of R¹ to the fused bicyclic ring represented by the formula (I).Also, the term “N-linked” of the “optionally substituted N-linkedheteroaryl group” means that R¹ is linked via a nitrogen atom of theheteroaryl group of R¹ to the fused bicyclic ring represented by theformula (I).

Examples of the “optionally substituted hydrocarbyl” for R¹ include thesame groups as those exemplified with respect to the optionallysubstituted hydrocarbyl of R³.

Examples of the “optionally substituted heterocyclic group” in the“optionally substituted C-linked heterocyclic group” for R¹ include thesame groups as those exemplified below with respect to the optionallysubstituted heterocyclic group of R².

Examples of the “heteroaryl group” in the “optionally substitutedN-linked heteroaryl group” for R¹ include a 5- to 10-membered aromaticheterocyclic group optionally containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in addition toone nitrogen atom (e.g., pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl,etc). Said heteroaryl group may be substituted with 1 to 3 substituentsselected from the group consisting of halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₆ alkoxy-C₁₋₆ alkyl, C₅₋₇ cycloalkyl, C₆₋₁₀ aryl (said aryl may have1 or 2 substituents selected from halogen, C₁₋₆ alkyl, halogeno C₁₋₆alkyl and C₁₋₆ alkoxy), C₇₋₁₄ aralkyl (said aralkyl may have 1 or 2substituents selected from halogen, C₁₋₆ alkyl, halogeno C₁₋₆ alkyl andC₁₋₆ alkoxy), hydroxy, hydroxy-C₁₋₆ alkyl, C₆₋₁₀ aryloxy (said aryloxymay have 1 or 2 substituents selected from halogen, C₁₋₆ alkyl, halogenoC₁₋₆ alkyl and C₁₋₆ alkoxy), C₇₋₁₄ aralkyloxy, C₆₋₁₀ aryl-carbonyl,carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, C₆₋₁₀ aryl-carbamoyl, amino,C₆₋₁₀ aryl-carbonylamino, C₁₋₆ alkyl-carbonylamino, C₁₋₆alkoxy-carbonylamino, C₆₋₁₀ arylthio, C₆₋₁₀ arylsulfonyl, cyano, 5- to7-membered heterocyclic group and oxo.

Examples of the “acyl” for R¹ include the same groups as thoseexemplified with respect to the acyl of R³.

Among these, R¹ in the formula (I) and (I′) is preferably an optionallysubstituted acyclic branched C₃₋₁₄ hydrocarbyl (preferably acyclicbranched C₃₋₇ hydrocarbyl such as 2-propyl, 3-hexyl, 3-pentyl, 4-heptyl,etc.), an optionally substituted C₆₋₁₀ aryl, an optionally substitutedC-linked 5- to 14-membered heterocyclic group or N-linked 5- to10-membered heteroaryl group.

R² in the formula (I) and (I′) is an optionally substituted cyclichydrocarbyl or an optionally substituted heterocyclic group.

Examples of the “cyclic hydrocarbyl” of the “optionally substitutedcyclic hydrocarbyl” for R² include a C₃₋₇ cycloalkyl group (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc), aC₃₋₇ cycloalkenyl group (e.g., 1-cyclopentenyl, 2-cyclopentenyl,3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, etc), an aryl grouphaving 6-10 carbon atoms (including that where a 5- to 6-memberednon-aromatic hydrocarbon ring is fused with phenyl group) such asphenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl,5-indanyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl,5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl,5,6-dihydro-4-naphthyl, etc.; and the like.

Examples of the “heterocyclic” of the “optionally substitutedheterocyclic group” for R² include (i) a 5- to 7-membered heterocyclicgroup containing one sulfur atom, one nitrogen atom or one oxygen atom,(ii) a 5- to 6-membered heterocyclic group containing 2-4 nitrogenatoms, (iii) a 5- to 6-membered heterocyclic group containing 1-2nitrogen atoms and one sulfur or oxygen atom, (iv) a 8- to 12-memberedfused bicyclic or tricyclic heterocyclic group containing 1-4heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom,and the like. In addition, each of the heterocyclic groups exemplifiedin (i) to (iv) may be a saturated or unsaturated heterocyclic group andthe unsaturated heterocyclic group may be either aromatic ornon-aromatic.

Examples of the heterocyclic group for an optionally substitutedheterocyclic group of R² include an aromatic monocyclic heterocyclicgroup and a non-aromatic heterocyclic group.

Specific examples of the heterocyclic group for an optionallysubstituted heterocyclic group include (i) an aromatic monocyclicheterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl, etc.) and (ii) a non-aromatic,heterocyclic group (e.g., oxiranyl, azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl,morpholinyl, thiomorpholinyl, piperazinyl, etc.), and (iii) a fusedheterocyclic group such as 8- to 12-membered bicyclic or tricyclicheterocyclic group (e.g., benzofuranyl, isobenzofuranyl, benzothienyl,indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl,1,2-benzoisooxazolyl, benzothiazolyl, benzopyranyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl,1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolinyl, etc.).

The above-mentioned “cycloalkyl”, “cycloalkenyl”, “aryl” and“heterocyclic group” in R² may have the same substituent as thoseexemplified with respect to the optionally substituted hydrocarbyl groupof R³ and further may have the same group as optionally substitutedhydrocarbyl group of R³ as their substituent.

In addition, two of the substituents of the “cyclic hydrocarbyl” in the“optionally substituted cyclic hydrocarbyl” or “heterocyclic group” inthe “optionally substituted heterocyclic group” for R² may be combinedeach other to form a fused ring with the cyclic hydrocarbyl orheterocyclic group. Examples of the fused ring include, for example, anaromatic fused heterocyclic group such as 8- to 12-membered aromaticfused heterocyclic group (preferably, heterocyclic group consisting ofthe above-mentioned 5- or 6-membered aromatic monocyclic heterocyclicgroup fused with a benzene ring or heterocyclic group consisting of theabove-mentioned 5- or 6-membered aromatic monocyclic heterocyclic groupfused with the same or different above-mentioned 5- or 6-memberedaromatic monocyclic heterocyclic group), etc. (e.g. benzofuranyl,isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl,benzindazolyl, benzoxazolyl, 1,2-benzoisooxazolyl, benzothiazolyl,benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.);etc.

Furthermore, the substituent of the “cyclic hydrocarbyl” in the“optionally substituted cyclic hydrocarbyl” or “heterocyclic group” inthe “optionally substituted heterocyclic group” for R² may be combinedtogether with the substituent: R⁴ of —NR⁴—, —NR⁴-alk-, —CONR⁴— or—NR⁴CO— in Z of formula (I) or (I′) to form a nitrogen-containing fusedring with the cyclic hydrocarbyl or heterocyclic group of R². Examplesof the fused ring include, for example, 8- to 12-membered bicyclicheterocyclic group formed by a fusion of a benzene ring with a saturatedmonocyclic heterocyclic group containing one nitrogen atom such as1,2,3,4-tetrahydroquinolyl, 2,3,4,5-tetrahydro-1H-1-benzazepinyl, andthe like.

The above-mentioned “fused ring” and “nitrogen-containing fused ring”may further have one to three substituents selected from an acyl (e.g.,acetyl, propionyl, etc.), an amide (e.g., dimethylaminocarbonyl,methylaminocarbonyl, etc.), an amine (e.g., dimethylamino, methylamino,amino, etc.), a halogen (e.g., fluorine, chlorine, bromine, etc.), alower alkyl (e.g., methyl, ethyl, trifluoromethyl, etc.) and a loweralkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, etc.), each of whichmay be substituted.

Among these, R² is preferably an optionally substituted C₆₋₁₀ aryl (morepreferably phenyl) or an optionally substituted 5- to 8-membered (morepreferably 5- to 6-membered) heterocyclic group (more preferablypyridyl) R² is more preferably phenyl which is 2,4-disubstituted,2,4,6-trisubstituted or 2,4,5-trisubstituted with two or threesubstituents, or pyridyl which is disubstituted or trisubstituted withtwo or three substituents. The substituents for the phenyl and pyridylmay be the same or different and examples thereof include an acyl (e.g.,acetyl, propionyl, etc.), an amide (e.g., dimethylaminocarbonyl,methylaminocarbonyl, etc.), an amine (e.g., dimethylamino, methylamino,amino, etc.), a halogen (e.g., fluorine, chlorine, bromine, etc.), alower alkyl (e.g., methyl, ethyl, trifluoromethyl, etc.) and a loweralkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, etc.), each of whichmay be substituted.

In the formula (I) and (I′), Y¹ is CR^(3a) or a nitrogen, Y² is CR^(3b)or a nitrogen, and Y³ is CR^(3c) or a nitrogen (wherein R^(3a), R^(3b)and R^(3c) are independently a hydrogen, a halogen, a nitro, a cyano, anoptionally substituted hydrocarbyl, an optionally substitutedhydrocarbyloxy, an optionally substituted hydrocarbylthio, an optionallysubstituted amino or an acyl), provided that one or less of Y¹, Y² andY³ is nitrogen.

The 6-membered ring with Y¹, Y² and Y³ of the formula (I) and (I′) is aring containing one or less nitrogen atom such as benzene ring andpyridine ring.

Examples of halogen include fluorine, chlorine, bromine, iodine, and thelike, preferably, chlorine and bromine.

Examples of the “optionally substituted hydrocarbyl” in R^(3a), R^(3b)and R^(3c) include the same groups as those exemplified with respect tothe optionally substituted hydrocarbyl of R³. Among them, an optionallysubstituted C₁₋₃ alkyl is preferred, and an unsubstituted C₁₋₃ alkyl,C₁₋₃ alkyl substituted with hydroxy and C₁₋₃ alkyl substituted with anamine (e.g., dimethylamino, methylamino, pyrrolidine, etc.) are morepreferred. Examples of the hydrocarbyl for said “optionally substitutedhydrocarbyloxy” and “optionally substituted hydrocarbylthio” of R^(3a),R^(3b) and R^(3c) include the same groups as those exemplified withrespect to the optionally substituted hydrocarbyl of R³. In particular,hydrocarbyl having 1 to 4 carbon atoms is preferred.

Among them, an optionally substituted C₁₋₃ alkoxy is preferred, and ansubstituted C₁₋₃ alkoxy and halogenated substituted C₁₋₃ alkoxy are morepreferred, and in particular, methoxy, difluoromethoxy andtrifluoromethoxy are preferred. Examples of the “optionally substitutedamino” for R^(3a), R^(3b) and R^(3c) include amino group, anN-mono-substituted amino group, and an N,N-di-substituted amino group.Examples of said substituted amino groups include that having one or twosubstituents of an optionally substituted hydrocarbyl group (e.g., aC₁₋₈ alkyl group, a C₃₋₇ cycloalkyl group, a C₂₋₈ alkenyl group, a C₂₋₈alkynyl group, a C₃₋₇ cycloalkenyl group, a C₆₋₁₀ aryl group that mayhave a C₁₋₄ alkyl group, etc.), an optionally substituted heterocyclicgroup (e.g., the same group as an optionally substituted heterocyclicgroup of R²), or the formula: —COR^(3d) (wherein R^(3d) representshydrogen atom or an optionally substituted hydrocarbyl group or anoptionally substituted heterocyclic group. As for “the hydrocarbylgroup” or “the heterocyclic group” in “an optionally substitutedhydrocarbyl group” or “an optionally substituted heterocyclic group” ofR^(3d) may have the same substituent as that of “the hydrocarbyl group”or “the heterocyclic group” in “an optionally substituted hydrocarbyl”of R³ or “an optionally substituted heterocyclic group” of R²),preferably a C₁₋₁₀ acyl group (e.g., a C₂₋₇ alkanoyl, benzoyl,nicotinoyl, etc.). Specific examples thereof include methylamino,dimethylamino, ethylamino, diethylamino, dipropylamino, dibutylamino,diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino,acetylamino, propionylamino, benzoylamino, nicotinoylamino, and thelike.

In addition, the two groups in said substituted amino groups may becombined to form a nitrogen-containing 5- to 7-membered ring (e.g.,piperidino, piperazino, morpholino, thiomorpholino, etc.).

Examples of the acyl for R^(3a), R^(3b) and R^(3c) include the samegroups as those exemplified with respect to the acyl for R³. Inparticular, an acyl having 2 to 4 carbon atoms is preferred.

In the formula (I) and (I′), Y¹, Y² and Y³ are preferably CR^(3a),CR^(3b) and CR^(3c) respectively, or one of Y¹, Y² and Y³ is nitrogen.R^(3a), R^(3b) and R^(3c) are preferably hydrogen, halogen, cyano, acyl,C₁₋₄ alkyl optionally substituted by hydroxy (for example, methyl,ethyl, hydroxymethyl), amino, and C₁₋₄ alkoxy (for example, methoxy,ethoxy). As R^(3a), chlorine, bromine, methoxy and methyl are morepreferred.

In the formula (I) and (I′), Z is a bond, —CO—, an oxygen (—O—), asulfur (—S—), —SO—, —SO₂—, —NR⁴—, —NR⁴-alk-, —CONR⁴— or —NR⁴CO—.

Said alk is an optionally substituted C₁₋₄ alkylene such as methylene,ethylene, propylene, butylene and the like.

R⁴ is a hydrogen, an optionally substituted hydrocarbyl or an acyl. The“optionally substituted hydrocarbyl” and “acyl” for R⁴ include the samegroups as those exemplified with respect to the optionally substitutedhydrocarbyl group and acyl for R³.

In addition, R⁴ may be combined together with the substituent of thecyclic hydrocarbyl or heterocyclic group in the optionally substitutedhydrocarbyl or optionally substituted heterocyclic group of R² to form aring. Examples of said ring include the same rings as those exemplifiedwith respect to the rings formed by the two substituents of R² mentionedabove.

Provided that

-   (i) the compound wherein X is —NH—, and R² is an optionally    substituted thiophene ring,-   (ii) the compound wherein R¹ is cyano, R^(3c) is methyl substituted    with three substituents, one of which is acyl, and other two of    which may form a ring,-   (iii) a)    6-amino-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazole-7-carbonitrile,-   b)    N-{7-cyano-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazol-6-yl}acetamide,-   c)    6-amino-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazole-7-carboxamide,    and-   d)    6-{[(allylamino)carbonothioyl]amino}-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazole-7-carboxamide,-   (iv)    4-({2-[(4-chlorophenyl)amino]-1,7-dimethyl-1H-benzimidazol-5-yl}oxy)-N-methylpyridine-2-carboxamide,-   (v)    N-[3,5-bis(trifluoromethyl)phenyl]-7-methyl-1H-benzimidazol-2-amine,-   (vi) the compound wherein R³ is substituted heteroarylmethyl, R² is    4-piperidinyl bearing a substituent at the 1-position,-   (vii) 6-chloro-4-methyl-N-piperidin-4-yl-1H-benzimidazol-2-amine,    and-   (viii) the compound wherein R² is substituted    8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-7-yl are excluded from the    compounds of the formula (I).

As a preferred compound of the formula (I) and (I′), a compound whereinX is NR³ (wherein R³ is preferably methyl, ethyl, hydroxyethyl, etc.);Y¹ is CR^(3a) (wherein R^(3a) is preferably H, Me, halogen (eg. F, Cl,Br), cyano, acyl, alkoxy, etc.), Y² is CR^(3b) (wherein R^(3b) ispreferably H, Me, halogen (eg. F, Cl, Br), etc.) or nitrogen and Y³ isCR^(3c) (wherein R^(3c) is preferably H, Me, halogen (eg. F, Cl, Br),etc.) or nitrogen; Z is NR⁴ (wherein R⁴ is preferably H, C₁₋₄ alkyl,etc.) or oxygen; R¹ is an optionally substituted acyclic branched C₃₋₇hydrocarbyl (in particular, 2-propyl, 3-hexyl, 3-pentyl, 4-heptyl); andR² is an optionally substituted C₆₋₁₀ aryl (in particular, phenyl, morepreferably di- or tri-substituted phenyl) or an optionally substitutedpyridyl (in particular, pyridyl, more preferably di- or tri-substitutedpyridyl) is exemplified. Among them, particularly preferred is thecompound wherein R¹ is 3-pentyl, 3-hexyl or 4-heptyl, X is NR³, R³ ismethyl, ethyl or hydroxyethyl, Y¹ is CR^(3a), Y² is CR^(3b), Y³ isCR^(3c), R^(3a) is chloro, bromo, methoxy or methyl, R^(3b) is ahydrogen, R^(3c) is a hydrogen, R² is phenyl which is2,4,6-trisubstituted, 2,4,5-trisubstituted or 2,4-disubstituted withsubstituents or pyridyl which is trisubstituted or disubstituted withsubstituents. Examples of the substituents for the phenyl and pyridylinclude an acyl such as acetyl and propionyl, an amide such asdimethylaminocarbonyl and methylaminocarbonyl, an amine such asdimethylamino, methylamino and amino, a halogen such as fluoro, chloroand bromo, a lower alkyl such as methyl, ethyl and trifluoromethyl and alower alkoxy such as methoxy, ethoxy and trifluoromethoxy, each of whichmay be substituted.

Compound (I) or (I′) may be in the form of a prodrug thereof. Theprodrug of compound (I) or (I′) refers to a compound that is convertedinto compound (I) or (I′) by a reaction with an enzyme, gastric acid, orthe like under a physiological condition in the living body, namely, (i)a compound that is converted into compound (I) or (I′) by an enzymaticoxidation, reduction, hydrolysis, or the like, and (ii) a compound thatis converted into compound (I) or (I′) by hydrolysis with gastric acidor the like. Examples of a prodrug of compound (I) or (I′) to be usedinclude a compound or its salt wherein hydroxyl group in compound (I) or(I′) is acylated, alkylated, phosphorylated, or converted into borate(e.g., a compound or its salt wherein hydroxyl group in compound (I) or(I′) is converted into acetyloxy, palmitoyloxy, propanoyloxy,pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy,dimethylaminomethylcarbonyloxy, etc.), a compound or its salt whereincarboxyl group in compound (I) or (I′) is esterified or amidated (e.g.,a compound or its salt wherein carboxyl group in compound (I) or (I′) issubjected to ethyl esterification, phenyl esterification,carboxyoxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methylesterification, cyclohexyloxycarbonyl esterification, or conversion intothe methyl amide, etc.), or the like. These prodrugs can be producedaccording to a per se known method or its modified method.

Further, a prodrug of compound (I) or (I′) may be a compound or its saltthat is converted into compound (I) or (I′) under physiologicalconditions as described in “Development of Drugs”, Volume 7, MolecularDesign, Hirokawa Shoten, 1990; pages 163-198.

General Synthetic Method

Production of a compound of formula (I) or a salt thereof of the presentinvention is discussed below. The following examples are given toillustrate the invention and are not intended to be inclusive in anymanner. Alternative methods may be employed by one skilled in the art.

A process for preparing compound (I) or a salt thereof of the presentinvention is shown in the following methods.

wherein R^(1a) is an optionally substituted hydrocarbyl, an optionallysubstituted C-linked heterocyclic, an optionally substituted N-linkedheteroaryl and acyl, Ar is an optionally substituted aryl, L¹ is aleaving group (for example, halogen atom such as chlorine, bromine andiodine, etc, sulfonyloxy group such as p-toluenesulfonyloxy group,methanesulfonyloxy group and trifluoromethanesulfonyloxy group, etc.,and acyloxy group such as acetyloxy group and benzoyloxy group, etc.)and each of other symbols has a meaning defined above.

Compound (III) or a salt thereof can be prepared by halogenation,sulfonylation or acylation of compound (II) or a salt thereof with ahalogenation agent, sulfonylation agent or acylation agent,respectively.

Examples of a halogenation agent include phosphorous oxychloride,phosphorous oxybromide, phosphorous trichloride, phosphorous tribromide,phosphorous pentachloride, chlorine, bromine and thionyl chloride. Thehalogenation agent is employed in an amount of 1 moles to excess per 1mole of compound (II) or as a solvent.

Examples of solvent having no adverse effect on the reaction includearomatic hydrocarbons such as benzene, toluene and xylene, ethers suchas diethyl ether, dioxane and tetrahydrofuran, esters such as ethylacetate, nitrites such as acetonitrile, halogenated hydrocarbon such aschloroform and dichloromethane, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones such asacetone and 2-butanone and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio.

While the reaction temperature may vary depending on compound (II) or asalt thereof employed as well as other conditions, it is 0 to 200° C.,preferably 20 to 150° C. The reaction time is 10 minutes to 24 hours,preferably 30 minutes to 12 hours.

The thus obtained compound (III) can be isolated and purified by theknown isolating and purifying methods, for example, concentration underreduced pressure, extraction with solvent, crystallization,recrystallization, transfer dissolution and chromatography.

When L¹ is a sulfonyloxy or an a acyloxy group in compound (III) or asalt thereof, compound (III) or a salt thereof can be prepared byreacting compound (II) with a sulfonylation agent or an acylation agentafter base treatment of compound (II).

A base may for example be an alkaline metal hydroxide such as sodiumhydroxide and potassium hydroxide, etc., an alkaline metal hydrogencarbonate such as sodium hydrogen carbonate and potassium hydrogencarbonate, etc., an alkaline metal carbonate such as sodium carbonateand potassium carbonate, etc., a cesium salt such as cesium carbonate,etc., an alkaline metal hydride such as sodium hydride and potassiumhydride, etc., sodium amide, an alkoxide such as sodium methoxide andsodium ethoxide, etc., an amine such as trimethylamine, triethylamineand diisopropylethylamine, etc., a cyclic amine such as pyridine, etc.

Examples of a sulfonylation agent include p-toluenesulfonyl chloride,methanesulfonylchloride, trifluoromethanesulfonylchloride, etc. Thesulfonylation agent is employed in an amount of 1 to 10 moles,preferably 1 to 5 moles per 1 mole of compound (II).

Examples of an acylation agent include acetylchloride, benzoyl chloride,etc. The acylation agent is employed in an amount of 1 to 10 moles,preferably 1 to 5 moles per 1 mole of compound (II).

Examples of the solvent having no adverse effect on the reaction includewater, alcohols such as methanol and ethanol, ethers such as diethylether, dioxane and tetrahydrofuran, aromatic hydrocarbons such asbenzene, toluene and xylene, esters such as ethyl acetate, halogenatedhydrocarbons such as chloroform and dichloromethane, nitrites such asacetonitrile, amides such as N,N-dimethylformamide andN,N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio.

While the reaction temperature may vary depending on compound (II) or asalt thereof employed as well as other conditions, it is 0 to 200° C.,preferably 0 to 150° C. The reaction time is 10 minutes to 24 hours,preferably 30 minutes to 12 hours.

The thus obtained compound (III) can be isolated and purified by theknown isolating and purifying methods, for example, concentration underreduced pressure, extraction with solvent, crystallization,recrystallization, transfer dissolution and chromatography.

Compound (Ia) or a salt thereof, which is encompassed within compound(I) of the invention, can be prepared by reacting compound (III) withArZH.

In this step, 1 to 20 moles, preferably 1 to 10 moles of a compoundrepresented by ArZH or a salt thereof are employed per 1 mole ofcompound (III) or a salt thereof.

This reaction may be performed under basic conditions. A base may forexample be an alkaline metal hydroxide such as sodium hydroxide andpotassium hydroxide, etc., an alkaline metal hydrogen carbonate such assodium hydrogen carbonate and potassium hydrogen carbonate, etc., analkaline metal carbonate such as sodium carbonate and potassiumcarbonate, etc., a cesium salt such as cesium carbonate, etc., analkaline metal hydride such as sodium hydride and potassium hydride,etc., sodium amide, an alkaline metal alkoxide such as sodium methoxide,sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, etc.,an amine such as trimethylamine, triethylamine anddiisopropylethylamine, etc., a cyclic amine such as pyridine, etc.

Examples of solvent having no adverse effect on the reaction includewater, alcohols such as methanol and ethanol, ethers such as diethylether, dioxane and tetrahydrofuran, aromatic hydrocarbons such asbenzene, toluene and xylene, esters such as ethyl acetate, halogenatedhydrocarbons such as chloroform and dichloromethane, nitrites such asacetonitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones such asacetone and 2-butanone and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio, or may not beused.

While the reaction temperature may vary depending on compound (III) or asalt thereof employed as well as other reaction conditions, it is 0 to200° C., preferably 20 to 150° C., or the reaction may be heated bymicrowave irradiation. The reaction time is 5 minutes to 48 hours,preferably 5 minutes to 24 hours.

The thus obtained compound (Ia) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

wherein R⁵ is hydrogen and an optionally substituted hydrocarbyl, R³ andR⁵ may be combined each other to form a ring, R⁶ and R⁷ are optionallysubstituted hydrocarbyl, L² and L³ are halogen atoms such as chlorine,bromine and iodine and each of other symbols has a meaning definedabove.

Compound (IIa) or a salt thereof can be prepared by treatment ofcompound (IV) with 1,1′-carbonyl diimidazole, phosgene, triphosgene,alkyl haloformate such as ethyl chloroformate, phenyl haloformate suchas phenyl chloroformate or urea, etc. Compound (IV) or a salt thereof ismainly commercially available or can be prepared from the nitroderivatives corresponded to compound (IV).

In this step, 1 to 5 moles, preferably 1 to 3 moles of an agent forcyclization or a salt thereof are employed per 1 mole of compound (IV)or a salt thereof.

Examples of solvent having no adverse effect on the reaction includewater, alcohols such as methanol and ethanol, ethers such as diethylether, dioxane and tetrahydrofuran, aromatic hydrocarbons such asbenzene, toluene and xylene, esters such as ethyl acetate, halogenatedhydrocarbons such as chloroform and dichloromethane, nitriles such asacetonitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones such asacetone and 2-butanone and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio, or may not beused.

While the reaction temperature may vary depending on compound (IV) or asalt thereof employed as well as other reaction conditions, it is 0 to150° C., preferably 20 to 100° C. The reaction time is 5 minutes to 48hours, preferably 5 minutes to 24 hours.

The thus obtained compound (IIa) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

Compound (IIb) or a salt thereof can be prepared by Grinard reaction ofcompound (IIa) or a salt thereof with R⁶MgL² and R⁷MgL³. When R⁶ isequal to R⁷ in compound (IIb), R⁶MgL² may be used in this step. When R⁶is not equal to R⁷ in compound (IIb), the Grinard reactions may beperformed stepwise by R⁶MgL² and R⁷MgL³ in this step.

In this step, 1 to 20 moles, preferably 1 to 10 moles of a compoundrepresented by R⁶MgL² and R⁷MgL³ or a salt thereof are employed per 1mole of compound (IIa) or a salt thereof.

Examples of solvent having no adverse effect on the reaction includeethers such as diethyl ether, dioxane and tetrahydrofuran, aromatichydrocarbons such as benzene, toluene and xylene, halogenatedhydrocarbons such as chloroform and dichloromethane, ketones such asacetone and 2-butanone and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio, or may not beused.

While the reaction temperature may vary depending on compound (IIa) or asalt thereof employed as well as other reaction conditions, it is −20 to150° C., preferably 0 to 100° C. The reaction time is 5 minutes to 24hours, preferably 5 minutes to 12 hours.

The thus obtained compound (IIb) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

Compound (IIc) or a salt thereof can be prepared by dehydration ofcompound (IIb) or a salt thereof with an acid, and the olefine is thenreduced by an appropriate reducing agent or catalytic hydrogenation.

An acid may for example be an inorganic acid such as hydrochloric acid,sulfuric acid, nitric acid and thionyl chloride, etc., and an ordinaryorganic acid such as formic acid, acetic acid, trifluoroacetic acid andmethanesulfonic acid, etc. as well as a Lewis acid.

In dehydration step, 1 mole to excess of an acid is employed per 1 moleof compound (IIb) or a salt thereof or an acid may be employed as asolvent.

Examples of solvent having no adverse effect on the reaction includewater, alcohols such as methanol and ethanol, ethers such as diethylether, dioxane and tetrahydrofuran, aromatic hydrocarbons such asbenzene, toluene and xylene, esters such as ethyl acetate, halogenatedhydrocarbons such as chloroform and dichloromethane, nitrites such asacetonitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones such asacetone and 2-butanone and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio, or may not beused.

While the reaction temperature may vary depending on compound (IIb) or asalt thereof employed as well as other reaction conditions, it is 0 to200° C., preferably 20 to 150° C. The reaction time is 5 minutes to 48hours, preferably 5 minutes to 24 hours.

The thus obtained olefine can be isolated and purified by the knownisolating and purifying methods, for example, concentration,concentration under reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

In reduction step, a reducing agent is preferably sodium borohydride,lithium borohydride, sodium cyanoborohydride and sodiumtriacetoxyborohydride. Catalytic hydrogenation may be performed in thisstep. Examples of a catalyst include a palladium catalyst such aspalladium black, palladium oxide, palladium barium sulfate, palladium oncarbon, palladium hydroxide, a platinum catalyst such as platinum black,platinum oxide and platinum on carbon, or nickel catalyst such asreduced nickel, oxidized nickel, and Raney nickel.

In this step, 1 to 20 moles, preferably 1 to 10 moles of a reducingagent are employed per 1 mole of the olefine or a salt thereof.

Examples of solvent having no adverse effect on the reaction includewater, alcohols such as methanol and ethanol, ethers such as diethylether, dioxane and tetrahydrofuran, aromatic hydrocarbons such asbenzene, toluene and xylene, esters such as ethyl acetate, halogenatedhydrocarbons such as chloroform and dichloromethane, nitrites such asacetonitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones such asacetone and 2-butanone and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio.

While the reaction temperature may vary depending on the olefine or asalt thereof employed as well as other reaction conditions, it is 0 to150° C., preferably 0 to 100° C. The reaction time is 5 minutes to 48hours, preferably 5 minutes to 24 hours.

The thus obtained compound (IIc) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

wherein each symbol has a meaning defined above.

Preparation of compound (Ic) or a salt thereof, which is encompassedwithin compound (I) of the invention, from compound (Ib) or a saltthereof can be carried out similar to preparation of compound (IIb) inScheme 2.

Preparation of compound (Id) or a salt thereof, which is encompassedwithin compound (I) of the invention, from compound (Ic) or a saltthereof can be carried out similar to preparation of compound (IIc) inScheme 2.

wherein each symbol has a meaning defined above.

Preparation of compound (IId) or a salt thereof from compound (IIa) or asalt thereof can be carried out similar to preparation of compound (IIb)in Scheme 2.

wherein each symbol has a meaning defined above.

Preparation of compound (Ie) or a salt thereof, which is encompassedwithin compound (I) of the invention, from compound (Ib) or a saltthereof can be carried out similar to preparation of compound (IIb) inScheme 2.

wherein R^(1b) is an optionally substituted hydrocarbyl and anoptionally substituted C-linked heterocyclic, R^(1c) is an optionallysubstituted hydrocarbyl, an optionally substituted C-linked heterocyclicand an optionally substituted N-linked heteroaryl, R⁸ and R⁹ areindependently hydrogen, optionally substituted hydrocarbyl, hydroxy andoptionally substituted alkoxy and may be combined each other to form aring,

is a heteroaryl, L⁴ is a halogen atom such as chlorine, bromine andiodine each of other symbols has a meaning defined above.

Compound (VI) or a salt thereof can be prepared by halogenation ofcompound (V) or a salt thereof with a halogenation agent.

Examples of a halogenation agent include chlorine, bromine, iodine,thionyl chloride, copper(I) chloride, copper(II) chloride, copper(I)bromide, copper(II) bromide, sodium chloride, sodium bromide, sodiumiodide, potassium iodide, etc. The halogenation agent is employed in anamount of 0.5 moles to 10 moles, preferably 0.5 moles to 5 moles, per 1mole of compound (V).

In this step, the diazonium type compound may be produced beforeintroduction of a halogen atom. Examples of an agent to produce thediazonium type compound include sodium nitrite, potassium nitrite andtert-butyl nitrite, etc. The agent is employed in an amount of 1 mole to10 moles, preferably 1 mole to 5 moles, per 1 mole of compound (V).

This reaction can be carried out under an acidic condition. Examples ofan acid include an inorganic acid such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, a nitric acid and copper sulfate,etc., as well as Lewis acid. An acid is employed in an amount of 2 molesto excess per 1 mole of compound (V).

Examples of solvent having no adverse effect on the reaction includewater, alcohols such as methanol and ethanol, ethers such as diethylether, dioxane and tetrahydrofuran, aromatic hydrocarbons such asbenzene, toluene and xylene, esters such as ethyl acetate, halogenatedhydrocarbons such as chloroform and dichloromethane, nitrites such asacetonitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones such asacetone and 2-butanone and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio.

While the reaction temperature may vary depending on compound (V) or asalt thereof employed as well as other conditions, it is −20 to 150° C.,preferably 0 to 100° C. The reaction time is 10 minutes to 24 hours,preferably 30 minutes to 12 hours.

The thus obtained compound (VI) can be isolated and purified by theknown isolating and purifying methods, for example, concentration underreduced pressure, extraction with solvent, crystallization,recrystallization, transfer dissolution and chromatography.

When R^(1c) is an optionally substituted hydrocarbyl, an optionallysubstituted C-linked heterocyclic in compound (IIe) or a salt thereof,compound (IIe) or a salt thereof can be prepared by reacting compound(VI) with R^(1b)BR⁸R⁹ or a salt thereof in the presence of a palladiumcatalyst, preferably tetrakis(triphenylphosphine)palladium(0) andtris(dibenzylidenacetate)dipalladium(0), a catalytic amount of aphosphine ligand, preferably 2-(dicyclohexylphosphino)biphenyl,2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (S-Phos) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-Phos)and a base according to the procedure of Suzuki coupling (OrganicSynthesis via Boranes, vol. 3: Suzuki coupling, A. Suzuki and H. C.Brown, Aldrich, 2002) and the modified methods, or a trialkyl aryl tinsuch as aryl trimethyltin or aryl tributyltin, etc. or a salt thereofand optional additives according to the procedure of Stille coupling(Angew. Chem. Int. Ed. Engl., 25, 504 (1986)) and the modified methods.

When R^(1c) is

in compound (IIe), compound (IIe) or a salt thereof can be also preparedby reacting compound (VI) or a salt thereof with

or a salt thereof in the presence of a palladium catalyst, preferablypalladium (II) acetate or a copper agent, preferably copper(II) acetate.A catalytic amount of a phosphine ligand, preferably2-(dicyclohexylphosphino)biphenyl, may be employed. This reaction can becarried out according to the procedure of Buchwald et al. (J. Am. Chem.Soc. 1998, 120, 9722) and Lam et. al. (Tetrahedron Lett., 1998, 39,2941) and the modified methods.

wherein each symbol has a meaning defined above.Compound (VII) or a salt thereof can be prepared by reaction of compound(VI) or a salt thereof via lithiation or coupling reaction with a boronagent.

When the reaction is performed via lithiation, examples of a boron agentinclude trialkyl borate, preferably triisopropyl borate.

In this step, 1 to 10 moles, preferably 1 to 5 moles of a boron agentare employed per 1 mole of compound (VI) or a salt thereof.

A lithiation agent may for example be alkyl lithium, preferably n-butyllithium, sec-butyl lithium and tert-butyl lithium and is employed in anamount of 1 to 5 moles, preferably 1 to 0.3 moles per 1 mole of compound(VI) or a salt thereof.

Examples of solvent having no adverse effect on the reaction includearomatic hydrocarbons such as benzene, toluene and xylene, ethers suchas diethyl ether, dioxane and tetrahydrofuran, and halogenatedhydrocarbon such as chloroform and dichloromethane. These solvents maybe used by mixing at an appropriate ratio.

While the reaction temperature may vary depending on compound (VI) or asalt thereof employed as well as other conditions, it is −100 to 100°C., preferably −80 to 50° C. The reaction time is 10 minutes to 24hours, preferably 30 minutes to 12 hours.

When the coupling reaction using a metal catalyst is carried out,examples of a boron agent include4,4,5,5-tetramethyl-1,3,2-dioxaborolane and bis(pinacolato)diborane. Inthis step, 1 to 10 moles, preferably 1 to 5 moles of a boron agent areemployed per 1 mole of compound (VI) or a salt thereof.

A palladium catalyst, preferably palladium(II) diacetate, a catalyticamount of a phosphine ligand, preferably2-(dicyclohexylphosphino)biphenyl and a base can be employed accordingto the procedure described in J. Org. Chem., 62, 6458 (1997) and themodified methods.

Examples of solvent having no adverse effect on the reaction includewater, alcohols such as methanol and ethanol, ethers such as diethylether, dioxane and tetrahydrofuran, aromatic hydrocarbons such asbenzene, toluene and xylene, esters such as ethyl acetate, halogenatedhydrocarbons such as chloroform and dichloromethane, nitrites such asacetonitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones such asacetone and 2-butanone and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio, or may not beused.

While the reaction temperature may vary depending on compound (VI) or asalt thereof employed as well as other conditions, it is 0 to 200° C.,preferably 20 to 150° C. The reaction time is 10 minutes to 48 hours,preferably 30 minutes to 24 hours.

The thus obtained compound (VII) can be isolated and purified by theknown isolating and purifying methods, for example, concentration underreduced pressure, extraction with solvent, crystallization,recrystallization, transfer dissolution and chromatography.

Preparation of compound (IIe) or a salt thereof from compound (VII) or asalt thereof can be carried out similar to preparation of compound (IIe)in Scheme 6.

wherein each symbol has a meaning defined above.

Preparation of compound (VIII) or a salt thereof from compound (VI) or asalt thereof can be carried out similar to preparation of compound (III)or a salt thereof in Scheme 1.

Preparation of compound (IX) or a salt thereof from compound (VIII) or asalt thereof can be carried out similar to preparation of compound (Ia)or a salt thereof in Scheme 1.

Preparation of compound (If) or a salt thereof, which is encompassedwithin compound (I) of the invention, from compound (IX) or a saltthereof can be carried out similar to preparation of compound (IIe) or asalt thereof in Scheme 6.

wherein R¹⁰ and R¹¹ are hydrogen and optionally substituted hydrocarbyland each of other symbols has a meaning defined above.

Compound (X) or a salt thereof can be prepared by reaction of compound(V) or a salt thereof with sodium nitrite, and the obtained diazoniumsalt is reduced by an appropriate reducing agent.

In this step, 1 to 5 moles, preferably 1 to 3 moles of sodium nitriteare employed per 1 mole of compound (V) or a salt thereof.

Examples of a reducing agent include alkaline metal borohydride,preferably sodium borohydride, lithium borohydride, sodiumcyanoborohydride and sodium triacetoxyborohydride, metal, preferably Fe,Zn, Sn and SnCl₂ and metal catalyst, a palladium catalyst such aspalladium black, palladium oxide, palladium barium sulfate, palladium oncarbon, palladium hydroxide, a platinum catalyst such as platinum black,platinum oxide and platinum on carbon, or nickel catalyst such asreduced nickel, oxidized nickel, and Raney nickel. The reducing agent isemployed in an amount of catalytic amount to excess per 1 mole ofcompound (V).

Examples of solvent having no adverse effect on the reaction includewater, alcohols such as methanol and ethanol, ethers such as diethylether, dioxane and tetrahydrofuran, aromatic hydrocarbons such asbenzene, toluene and xylene, esters such as ethyl acetate, halogenatedhydrocarbons such as chloroform and dichloromethane, nitrites such asacetonitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, and sulfoxides suchas dimethylsulfoxide. These solvents may be used by mixing at anappropriate ratio, or may not be used.

While the reaction temperature may vary depending on compound (V) or asalt thereof employed as well as other conditions, it is −20 to 150° C.,preferably 0 to 100° C. The reaction time is 10 minutes to 24 hours,preferably 30 minutes to 12 hours.

The thus obtained compound (X) can be isolated and purified by the knownisolating and purifying methods, for example, concentration underreduced pressure, extraction with solvent, crystallization,recrystallization, transfer dissolution and chromatography.

Compound (IIf) or a salt thereof can be prepared by reaction of compound(X) or a salt thereof with compound (XI) or a salt thereof.

In this step, 1 to 5 moles, preferably 1 to 3 moles of compound (XI) ora salt thereof are employed per 1 mole of compound (X) or a saltthereof.

An acid may be used and for example be an inorganic acid such ashydrochloric acid, sulfuric acid and nitric acid, etc., and an ordinaryorganic acid such as formic acid, acetic acid, p-toluenesulfonic acid,trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewisacid.

Examples of solvent having no adverse effect on the reaction includewater, alcohols such as methanol and ethanol, ethers such as diethylether, dioxane and tetrahydrofuran, aromatic hydrocarbons such asbenzene, toluene and xylene, esters such as ethyl acetate, halogenatedhydrocarbons such as chloroform and dichloromethane, nitrites such asacetonitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, acids such as formicacid and acetic acid and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio.

While the reaction temperature may vary depending on compound (V) or asalt thereof employed as well as other conditions, it is 0 to 200° C.,preferably 20 to 150° C. The reaction time is 10 minutes to 24 hours,preferably 30 minutes to 12 hours.

The thus obtained compound (IIf) can be isolated and purified by theknown isolating and purifying methods, for example, concentration underreduced pressure, extraction with solvent, crystallization,recrystallization, transfer dissolution and chromatography.

wherein each symbol has a meaning defined above.

Preparation of compound (IIg) or a salt thereof from compound (V) or asalt thereof can be carried out similar to preparation of compound (IIf)or a salt thereof in Scheme 9.

wherein R¹² is an optionally substituted C₁₋₆ alkylcarbonyl (forexample. formyl, methylcarbonyl and ethylcarbonyl, etc.),phenylcarbonyl, a C₁₋₆ alkyloxycarbonyl (for example, methoxycarbonyl,ethoxycarbonyl and tert-butoxycarbonyl, etc.), phenyloxycarbonyl (forexample, benzoxycarbonyl), C₇₋₁₀ aralkylcarbonyl (for example,benzyloxycarbonyl), C₇₋₁₀ aralkyl (for example, benzyl and4-methoxybenzyl, etc.), trityl, phthaloyl, etc. A substituent on each ofthe groups listed above may be a halogen atom (for example, fluorine,chlorine, bromine and iodine, etc.), a C₁₋₆ alkylcarbonyl (for example,methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.) and a nitrogroup, and each of other symbols has a meaning defined above.

Compound (IIa) or a salt thereof can be also prepared by the procedureas shown in scheme 11.

Compound (XIV) or a salt thereof can be prepared by nitration ofcompound (XIII) or a salt thereof with a nitration agent. Compound(XIII) or a salt thereof is mainly commercially available or can beprepared from the aniline derivatives corresponded to compound (XIII) bya usual acetylation method.

Examples of a nitration agent include nitric acids (for example, fumingnitric acid, a solution of nitric acid and sulfuric acid etc.), nitrates(for example, sodium nitrate, potassium nitrate, silver nitrate,ammonium nitrate, benzoyl nitrate, benzyltriphenylphosphonium nitrate,bismuth subnitrate, etc). The nitration agent is employed in an amountof 0.5 moles to 50 moles, or may be employed as a solvent, preferably0.5 moles to 30 moles, per 1 mole of compound (XIII).

This reaction is also carried out in the presence of additives. Examplesof additives include anhydrides (for example, acetic anhydride,trifluoroacetic anhydride, methanesulfonic anhydride, etc), acidchlorides (for example, thionyl chloride, etc), acids

(for example, acetic acid, methanesulfonic acid, etc), metals (forexample, iron, etc).

The additives are employed in an amount of 0.5 moles to 50 moles,preferably 0.5 moles to 30 moles, per 1 mole of compound (XIII).

Examples of solvent having no adverse effect on the reaction includewater, acetic acid, halogenated hydrocarbons such as chloroform anddichloromethane, 1,2-dichloroethane, etc. These solvents may be used bymixing at an appropriate ratio, or may not be used. While the reactiontemperature may vary depending on compound (XIII) or a salt thereofemployed as well as other reaction conditions, it is −20 to 150° C.,preferably 0 to 100° C. The reaction time is 5 minutes to 48 hours,preferably 5 minutes to 24 hours. The thus obtained compound (XIV) canbe isolated and purified by the known isolating and purifying methods,for example, concentration, concentration under reduced pressure,extraction with solvent, crystallization, recrystallization, transferdissolution and chromatography.

Compound (XV) or a salt thereof can be prepared by deacetylation ofcompound (XIV) or a salt thereof with an acid or base, and thenreduction of the nitro group by an appropriate reducing agent orcatalytic hydrogenation.

An acid may for example be an inorganic acid such as hydrochloric acid,sulfuric acid, nitric acid and thionyl chloride, etc., and an ordinaryorganic acid such as formic acid, acetic acid, trifluoroacetic acid andmethanesulfonic acid, etc. as well as a Lewis acid.

A base may for example be an alkaline metal hydroxide such as sodiumhydroxide and potassium hydroxide, etc., an alkaline metal hydrogencarbonate such as sodium hydrogen carbonate and potassium hydrogencarbonate, etc., an alkaline metal carbonate such as sodium carbonateand potassium carbonate, etc., a cesium salt such as cesium carbonate,etc., an alkaline metal hydride such as sodium hydride and potassiumhydride, etc., sodium amide, an alkaline metal alkoxide such as sodiummethoxide, sodium ethoxide, sodium tert-butoxide and potassiumtert-butoxide, etc.

In deacetylation step, 1 mole to excess of an acid or base is employedper 1 mole of compound (XIV) or a salt thereof, or an acid may beemployed as a solvent.

Examples of solvent having no adverse effect on the reaction includewater, alcohols such as methanol and ethanol, ethers such as diethylether, dioxane and tetrahydrofuran, aromatic hydrocarbons such asbenzene, toluene and xylene, esters such as ethyl acetate, halogenatedhydrocarbons such as chloroform and dichloromethane, nitrites such asacetonitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones such asacetone and 2-butanone and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio, or may not beused.

While the reaction temperature may vary depending on compound (XIV) or asalt thereof employed as well as other reaction conditions, it is 0 to200° C., preferably 20 to 150° C. The reaction time is 5 minutes to 48hours, preferably 5 minutes to 24 hours.

The thus obtained nitro compounds can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

In reduction step, a reducing agent is preferably sodium borohydride,lithium borohydride, sodium cyanoborohydride and sodiumtriacetoxyborohydride. Catalytic hydrogenation may be performed in thisstep. Examples of a catalyst include a palladium catalyst such aspalladium black, palladium oxide, palladium barium sulfate, palladium oncarbon, palladium hydroxide, a platinum catalyst such as platinum black,platinum oxide and platinum on carbon, or nickel catalyst such asreduced nickel, oxidized nickel, and Raney nickel.

In this step, 1 to 20 moles, preferably 1 to 10 moles of a reducingagent are employed per 1 mole of the nitro compounds or a salt thereof.

Examples of solvent having no adverse effect on the reaction includewater, alcohols such as methanol and ethanol, ethers such as diethylether, dioxane and tetrahydrofuran, aromatic hydrocarbons such asbenzene, toluene and xylene, esters such as ethyl acetate, halogenatedhydrocarbons such as chloroform and dichloromethane, nitrites such asacetonitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones such asacetone and 2-butanone and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio.

While the reaction temperature may vary depending on compound (XIV) or asalt thereof employed as well as other reaction conditions, it is 0 to150° C., preferably 0 to 100° C. The reaction time is 5 minutes to 48hours, preferably 5 minutes to 24 hours.

The thus obtained compound (XV) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

Preparation of compound (XVI) or a salt thereof from compound (XV) or asalt thereof can be carried out similar to preparation of compound (IIa)in Scheme 2.

Compound (XVII) or a salt thereof can be prepared by reacting compound(XVI) with R¹²-L² or anhydride(R¹²)₂O.

In this step, 1 to 10 moles, preferably 1 to 5 moles of a compoundrepresented by R¹²-L² or anhydride (R²)₂O or a salt thereof are employedper 1 mole of compound (XVI) or a salt thereof.

This reaction may be performed under basic conditions. A base may forexample be an alkaline metal hydroxide such as sodium hydroxide andpotassium hydroxide, etc., an alkaline metal hydrogen carbonate such assodium hydrogen carbonate and potassium hydrogen carbonate, etc., analkaline metal carbonate such as sodium carbonate and potassiumcarbonate, etc., a cesium salt such as cesium carbonate, etc., analkaline metal hydride such as sodium hydride and potassium hydride,etc., sodium amide, an alkaline metal alkoxide such as sodium methoxide,sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, etc.,an amine such as trimethylamine, triethylamine anddiisopropylethylamine, etc., a cyclic amine such as pyridine,4-dimethylaminopyridine, DBU, etc.

Examples of solvent having no adverse effect on the reaction includewater, alcohols such as methanol and ethanol, ethers such as diethylether, dioxane and tetrahydrofuran, aromatic hydrocarbons such asbenzene, toluene and xylene, esters such as ethyl acetate, halogenatedhydrocarbons such as chloroform and dichloromethane, nitrites such asacetonitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones such asacetone and 2-butanone and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio, or may not beused.

While the reaction temperature may vary depending on compound (XVI) or asalt thereof employed as well as other reaction conditions, it is 0 to200° C., preferably 20 to 150° C., or the reaction may be heated bymicrowave irradiation. The reaction time is 5 minutes to 48 hours,preferably 5 minutes to 24 hours.

The thus obtained compound (XVII) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

Preparation of compound (XVIII) or a salt thereof from compound (XVII)or a salt thereof can be carried out similar to preparation of compound(XVII).

Compound (IIa) or a salt thereof can be prepared by deprotection ofcompound (XVIII) or a salt thereof with an acid or a base, or catalytichydrogenation.

An acid may for example be an inorganic acid such as hydrochloric acid,sulfuric acid, nitric acid and thionyl chloride, etc., and an ordinaryorganic acid such as formic acid, acetic acid, trifluoroacetic acid andmethanesulfonic acid, etc. as well as a Lewis acid.

A base may for example be an alkaline metal hydroxide such as sodiumhydroxide and potassium hydroxide, etc., an alkaline metal hydrogencarbonate such as sodium hydrogen carbonate and potassium hydrogencarbonate, etc., an alkaline metal carbonate such as sodium carbonateand potassium carbonate, etc., a cesium salt such as cesium carbonate,etc., an alkaline metal hydride such as sodium hydride and potassiumhydride, etc., sodium amide, an alkaline metal alkoxide such as sodiummethoxide, sodium ethoxide, sodium tert-butoxide and potassiumtert-butoxide, etc.

Catalytic hydrogenation may be performed in this step. Examples of acatalyst include a palladium catalyst such as palladium black, palladiumoxide, palladium barium sulfate, palladium on carbon, palladiumhydroxide, a platinum catalyst such as platinum black, platinum oxideand platinum on carbon, or nickel catalyst such as reduced nickel,oxidized nickel, and Raney nickel.

In this step, 1 mole to excess of an acid or a base is employed per 1mole of compound (XVIII) or a salt thereof, or an acid may be employedas a solvent.

Examples of solvent having no adverse effect on the reaction includewater, alcohols such as methanol and ethanol, ethers such as diethylether, dioxane and tetrahydrofuran, aromatic hydrocarbons such asbenzene, toluene and xylene, esters such as ethyl acetate, halogenatedhydrocarbons such as chloroform and dichloromethane, nitrites such asacetonitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone, ketones such asacetone and 2-butanone and sulfoxides such as dimethylsulfoxide. Thesesolvents may be used by mixing at an appropriate ratio, or may not beused.

While the reaction temperature may vary depending on compound (XVIII) ora salt thereof employed as well as other reaction conditions, it is 0 to200° C., preferably 20 to 150° C. The reaction time is 5 minutes to 48hours, preferably 5 minutes to 24 hours.

The thus obtained compounds can be isolated and purified by the knownisolating and purifying methods, for example, concentration,concentration under reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

A starting compound for compound (I) according to the invention may bein a form of a salt, including a salt with an inorganic acid (forexample, hydrochloric acid, phosphoric acid, hydrobromic acid andsulfuric acid, etc.) and a salt with an organic acid (for example,acetic acid, formic acid, propionic acid, fumaric acid, maleic acid,succinic acid, tartaric acid, citric acid, malic acid, oxalic acid,benzoic acid, methanesulfonic acid and benzenesulfonic acid, etc.). Whenany of these compounds carries an acidic group such as —COOH, etc., asalt with an inorganic base (for example, an alkaline metal or analkaline earth metal such as sodium, potassium, calcium and magnesium,ammonia, etc.) or with an organic base (for example, tri-C₁₋₃ alkylaminesuch as triethylamine, etc.) may be formed.

In each of the reactions described above, when a starting compoundcarries as a substituent an amino group, an amide group, a hydrozinogroup, a urea group, a carboxyl group or a hydroxyl group, then suchgroup may be derivatized with a protective group employed ordinarily inpeptide chemistry, which is cleaved after a reaction if desired to yieldan intended compound.

A protective group for an amino group, an amide group and a urea groupmay for example be an optionally substituted C₁₋₆ alkylcarbonyl (forexample. formyl, methylcarbonyl and ethylcarbonyl, etc.),phenylcarbonyl, a C₁₋₆ alkyloxycarbonyl (for example, methoxycarbonyl,ethoxycarbonyl and tert-butoxycarbonyl, etc.), phenyloxycarbonyl (forexample, benzoxycarbonyl), C₇₋₁₀ aralkylcarbonyl (for example,benzyloxycarbonyl), C₇₋₁₀ aralkyl (for example, benzyl and4-methoxybenzyl, etc.), trityl, phthaloyl, etc. A substituent on each ofthe groups listed above may be a halogen atom (for example, fluorine,chlorine, bromine and iodine, etc.), a C₁₋₆ alkylcarbonyl (for example,methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.) and a nitrogroup, which may occur 1 to about 3 times.

A protective group for a carboxyl group may for example be an optionallysubstituted C₁₋₆ alkyl (for example, methyl, ethyl, n-propyl, i-propyl,n-butyl and t-butyl, etc.), phenyl, trityl and silyl, etc. A substituenton each of the groups listed above may be a halogen atom (for example,fluorine, chlorine, bromine and iodine, etc.), a C₁₋₆ alkylcarbonyl (forexample, formyl, methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.)and a nitro group, which may occur 1 to about 3 times.

A protective group for a hydroxyl group may for example be an optionallysubstituted C₁₋₆ alkyl (for example, methyl, ethyl, n-propyl, i-propyl,n-butyl and tert-butyl, etc.), phenyl, a C₇₋₁₀ aralkyl (for example,benzyl, etc.), a C₁₋₆ alkylcarbonyl (for example, formyl, methylcarbonyland ethylcarbonyl, etc.), phenyloxycarbonyl (for example,benzoxycarbonyl, etc.), C₇₋₁₀ aralkylcarbonyl (for example,benzyloxycarbonyl, etc.), pyranyl, furanyl, silyl, etc. A substituent oneach of the groups listed above may be a halogen atom (for example,fluorine, chlorine, bromine and iodine, etc.), a C₁₋₆ alkyl, phenyl, aC₇₋₁₀ aralkyl, nitro, etc., which may occur 1 to about 4 times.

A method for cleaving a protective group is a method known per se or ananalogous method, such as a treatment for example with an acid, a base,a reduction, UV light, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate,etc.

The pharmaceutical composition containing compound (I) or (I′) of thepresent invention is expected to be useful in the treatment andprevention of diseases, in which CRF is involved, such as depression,major depression, bipolar depression, dysthymia, seasonal affectivedisorder, recurrent depression, postpartum depression, suppressionsymptom, mania, anxiety, generalized anxiety disorder, anxiety syndrome,panic disorder, phobia, social phobia, obsessive-compulsive disorder,posttraumatic stress disorder, stress-induced insomnia, post psychictrauma stress disorder, Tourette's syndrome, autism, passion disorder,adjustment disorder, dysthymic disorder, sleep disorder, insomnia,bipolar disorder, circulatory disease, neurosis, schizophrenia,digestive ulcer, irritable bowl syndrome, inflammatory bowel disease,ulcerative colitis, Crohn's disease, stress-induced gastrointestinaldisorder, nervous emesis, peptic ulcer, diarrhea, constipation,postoperative ileus, gastrointestine dysfunction and nervous vomitingassociated with stress, Alzheimer's disease, Alzheimer's type seniledementia, nervous degenerated disease such as Parkinson's disease andHuntington's disease, multi-infarct dementia, senile dementia, nervousorexia inactivity, eating disorder, anorexia nervosa, hyperphagia andother ingestion disorder, obesity, diabetes, alcohol dependency,pharmacophinia, drug withdrawal, migraine, stress headache, tensionheadache, ischemic nervous disorder, nervous disorder, cerebralparalysis, progressive supranuclear palsy, amyotrophic lateralsclerosis, multiple sclerosis, muscular convulsion, chronic fatiguesyndrome, glaucoma, Meniere syndrome, autonomic imbalance, alopecia,hypertension, cardiovascular disorder, tachycardia, congestive heartattack, hyperplea, bronchial asthma, apnea, infant sudden deathsyndrome, inflammatory disorder, pain, allergic disorder, impotence,menopausal disorder, fertilization disorder, infertility, cancer, immunefunction abnormality at HIV infection, immune functional abnormality dueto stress, cerebrospinal meningitis, acromegaly, incontinence orosteoporosis.

Compound (I) or (I′) of the present invention can be formulated with apharmaceutically acceptable carrier and can be orally or parenterallyadministered as solid formulations such as tablets, capsules, granules,powders, or the like; or liquid formulations such as syrups, injections,or the like. Also, there can be prepared formulations for transdermaladministration such as patchings, cataplasms, ointments (includingcreams), plasters, tapes, lotions, liquids and solutions, suspensions,emulsions, sprays, and the like.

As for a pharmaceutically acceptable carrier, a variety of organic orinorganic carrier substances, which have been conventionally employed asformulation materials, is used and compounded as a bulking agent, alubricant, a binding agent, and a disintegrator in solid formulations; avehicle, a solubilizing agent, a suspending agent, an isotonicity agent,a buffering agent, and an analgesic in liquid formulations. Ifnecessary, formulation excipients such as a preservative, anantioxidant, a stabilizer, a coloring agent, a sweetening agent, and thelike can be used.

Preferred examples of the bulking agent include lactose, sucrose,D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid,and the like. Preferred examples of the lubricant include magnesiumstearate, potassium stearate, talc, colloidal silica, and the like.Preferred examples of the binding agent include crystalline cellulose,α-starch, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, and the like.Preferred examples of the disintegrator include starch, carboxymethylcellulose, calcium carboxymethyl cellulose, croscarmellose sodium,sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose,and the like. Preferred examples of the vehicle include water forinjection, alcohol, propylene glycol, macrogol, sesame oil, corn oil,and the like.

If necessary, for the purpose of taste masking, enteric coating, orprolonged action, oral formulations can be prepared by coating by a perse known method. Examples of this coating agent includehydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose,hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68[polyoxyethylene (160) polyoxypropylene (30) glycol], cellulose acetatephthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethylcellulose acetate phthalate, Eudragit (manufactured by Rohm Company,methacrylic acid-acrylic acid copolymer), and the like.

Preferred examples of the solubilizing agent include polyethyleneglycol, propylene glycol, benzyl benzoate, ethanol, trisamiomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate, and thelike. Preferred examples of the suspending agent include surface activeagents such as stearyltriethanolamine, sodium lauryl sulfate,laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride, glycerin monostearate, and the like; hydrophilic, highmolecular substances such as polyvinyl alcohol, polyvinyl pyrrolidone,sodium carboxymethyl cellulose, methyl cellulose, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and thelike; and so on. Preferred examples of the isotonicity agent includesodium chloride, glycerin, D-mannitol, and the like. Preferred examplesof the buffering agent include buffer solutions of a phosphate, anacetate, a carbonate, a citrate, or the like. Preferable examples of theanalgesic include benzyl alcohol and the like. Preferred examples of thepreservative include paraoxybenzoic acid esters, chlorobutanol, benzylalcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and thelike. Preferred examples of the antioxidant include sulfites, ascorbicacid, and the like.

The following examples and experiments describe the manner and processof making and using the present invention and are illustrative ratherthan limiting. It is to be understood that there may be otherembodiments which fall within the spirit and scope of the presentinvention as defined by the claims appended hereto.

In the following examples, preparative HPLC was carried out under acondition described below.

Equipment: Gilson high through put purification system

Column: YMC CombiPrep ODS-A S-5 μm, 50×20 mm

Solvent: A; 0.1% aqueous trifluoroacetic acid, B; 0.1% trifluoroaceticacid in acetonitrile

Gradient cycle: 0.00 min (A/B=95/5), 1.00 min (A/B=95/5), 5.20 min(A/B=5/95), 6.40 min (A/B=5/95), 6.50 min (A/B=95/5), 6.60 min(A/B=95/5)

Flow rate: 20 mL/min

Detection: UV 220 nm

Example 1N-(4-Bromo-2-methoxy-6-methylphenyl)-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amineHydrochloride

Methyl 2-chloro-3-nitrobenzoate

A slurry of 20 g (99 mmol) of 2-chloro-3-nitrobenzoic acid in 800 mLdichloromethane was cooled in an ice bath. Dimethylformamide (0.40 mL)was added to the reaction followed by drop wise addition of 13.85 g (109mmol) of oxalyl chloride. The reaction was allowed to warm to roomtemperature and was stirred for 6 h. Methanol (200 mL) was added dropwise and the reaction was stirred overnight. The reaction wasconcentrated to a residue, dissolved in dichloromethane and passedthrough a plug of silica eluting with a 50% ethyl acetate/hexanemixture. The filtrate was concentrated in vacuo to give 21.5 g (100%) ofthe title compound.

¹H NMR (CDCl₃) δ 3.98 (s, 3H), 7.48 (t, J=7.8 Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.95 (d, J=7.8 Hz, 1H).

Methyl 2-Methylamino-3-nitrobenzoate

A solution of 21.5 g (99.5 mmol) of methyl 2-chloro-3-nitrobenzoate in300 mL of tetrahydrofuran (THF) was treated with drop wise addition of300 mL (597 mmol) of methylamine (2M solution in THF) and was stirredovernight at room temperature. The reaction was concentrated to dryness,dissolved in dichloromethane, and washed with aqueous sodium bicarbonateand water. The organics were dried over sodium sulfate, filtered, andconcentrated in vacuo to give 20.8 g (100%) of the title compound.

¹H NMR (CDCl₃) δ 2.82 (d, J=5.5 Hz, 3H), 3.9 (s, 3H), 6.65 (t, J=7.8 Hz,1H), 7.97 (d, J=8.2 Hz, 1H), 8.04 (J=7.8 Hz, 1H), 8.57 (s, 1H).

MS Calcd.: 210. Found: 211 (M+H).

Methyl 3-amino-2-methylaminobenzoate

A solution of 20.7 g (98 mmol) of methyl 2-methylamino-3-nitrobenzoatein 1200 mL of methanol was inerted with nitrogen. To this solution wasadded 5 g (2.3 mmol) 10% palladium on carbon (50% wet). The reaction waspurged with hydrogen and stirred under balloon pressure hydrogen for 7h. The catalyst was removed by filtration and the filtrate wasconcentrated in vacuo to give 17.5 g (99%) of the title compound.

MS Calcd.: 180. Found: 181 (M+H).

Methyl 1-methyl-2-oxo-1,3-dihydro-1H-benzimidazole-7-carboxylate

To a solution of 17.5 g (97 mmol) of Methy 3-amino-2-methylaminobenzoatein 550 mL of tetrahydrofuran was added 20.5 g (146 mmol) of1,1′-carbonyldiimidazole and the reaction was stirred overnight at roomtemperature. The reaction was heated at 50° C. for 2 h and allowed tocool to room temperature overnight. The reaction was concentrated invacuo and the residue was dissolved in 1 L ethyl acetate and washed with400 mL of water. The organics were dried over sodium sulfate, filtered,and concentrated in vacuo to a residue. The residue was purified byflash chromatography eluting with a solution of 50% ethylacetate/dichloromethane to give 7.22 g (78%) of the title compound.

¹H NMR (CDCl₃) δ 3.59 (s, 3H), 3.95 (s, 3H), 7.08 (t, J=7.8 Hz, 1H),7.27 (d, J=7.8 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H).

MS Calcd.: 206. Found: 207 (M+H).

1-Methyl-7-(1-propylbutyl)-1,3-dihydro-2H-benzimidazol-2-one

A solution of 8.5 mL (17 mmol) of propylmagnesium chloride (2M solutionin diethyl ether) was diluted with 10 mL of diethyl ether and cooled inan ice bath. To this solution was slowly added 1.0 g (4.85 mmol) ofmethyl 1-methyl-2-oxo-1,3-dihydro-1H-benzimidazole-7-carboxylate and thereaction was stirred overnight at 35° C. The reaction was quenched with50 mL of methanol, 100 mL of water, and 10 mL of 1N aqueous hydrochloricacid. The aqueous mixture was extracted with 50 mL of diethyl ether andtwice with 50 mL of dichloromethane. The organics were combined, driedover sodium sulfate, filtered, and concentrated in vacuo to a residue.This residue was dissolved in 50 mL of ethanol and 10 mL of 6N aqueoushydrochloric acid was added. The mixture was heated at 75° C. for 2 hand then concentrated in vacuo. The resulting residue was dissolved indichloromethane and washed with aqueous sodium bicarbonate. The organicswere dried over sodium sulfate, filtered, and concentrated in vacuo togive 1.05 g of crude1-methyl-7-(1-propylbut-1-enyl)-1,3-dihydro-2H-benzimidazol-2-one, whichwas used without further purification in the next step. MS Calcd.: 244.Found: 245 (M+H). The crude material was dissolved in 50 mL of methanoland inerted with nitrogen. This solution was treated with 300 mg (2.16mmol) of 10% palladium on carbon (50% wet), purged with hydrogen, andstirred under balloon pressure hydrogen for 36 h. The catalyst wasremoved by filtration and the filtrate concentrated in vacuo. The cruderesidue thus obtained was purified by flash chromatography eluting witha mixture of 5% methanol/dichloromethane. The resulting impure mixturewas triturated with diethyl ether and filtered. The filtrate containedthe title compound along with a small amount of an unidentifiedimpurity, was concentrated in vacuo. The residue thus obtained (710 mg)was used in the next reaction without further purification.

MS Calcd.: 246. Found: 247 (M+H).

2-Chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazole

The crude 1-methyl-7-(1-propylbutyl)-1,3-dihydrobenzimidazol-2-one (710mg, 2.88 mmol) was dissolved in 10 mL of phosphorous oxychloride andheated at 100° C. overnight. The reaction was allowed to cool to roomtemperature and concentrated in vacuo. The residue thus obtained wasdissolved in ethyl acetate, washed with aqueous sodium bicarbonate,dried over sodium sulfate, filtered and concentrated in vacuo to give655 mg (86%) of the title compound, which was used in the next stepwithout further purification.

MS Calcd.: 264. Found: 265 (M+H).

N-(4-Bromo-2-methoxy-6-methylphenyl)-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amineHydrochloride

A neat mixture of 100 mg (0.38 mmol) of2-chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazole and 163 mg (0.76mmol) of 4-bromo-2-methoxy-6-methylphenylamine was heated at 100° C.overnight. The reaction was cooled to room temperature and the residuewas dissolved in 10 mL of dichloromethane, washed with water, dried oversodium sulfate, filtered, and concentrated in vacuo. This residue thusobtained was purified by preparative HPLC to give the title compound asthe trifluoroacetic acid salt. The salt was dissolved in methanol andtreated with hydrochloric acid (1N solution in diethyl ether). Thesolution was concentrated in vacuo to give 40 mg (23%) of the titlecompound as the hydrochloric salt.

¹H NMR (CDCl₃) δ 0.87 (t, J=7.4 Hz, 6H), 1.26 (m, 4H), 1.71 (m, 4H),2.12 (s, 3H), 3.40 (m, 1H), 3.82 (s, 3H), 3.89 (s, 3H), 6.93 (s, 1H),6.97-6.99 (m, 1H), 7.03 (s, 1H), 7.09 (t, J=7.2 Hz, 1H), 7.34 (br s,1H).

MS Calcd.: 443. Found: 444 (M+H).

Compounds described below were prepared in a similar method.

TABLE 1 Example Structure Name Physical Data 2

1-methyl-7-(1- propylbutyl)-N- (2,4,6- trimethoxyphenyl)- 1H-benzimidazol-2- amine Hydrochloride MS Calcd.: 411; Found: 412 (M + H).3

N-mesityl-1- methyl-7-(1- propylbutyl)- 1H- benzimidazol-2- amine ¹H NMR(CDCl₃) δ 0.87 (t, 6H, J = 7.0 Hz); 1.26 (br s, 6H); 1.67-1.70 (m, 4H);2.19 (s, 4H); 2.28 (s, 3H); 3.35 (br s, 1H); 3.73 (s, 3H); 5.56 (br s,1H); 6.92 (s, 3H); 7.07 (br s, 1H); 7.30 (br s, 1H); MS Calcd.: 363;Found: 364 (M + H). 4

N-(4-bromo-2- methoxy-6- methylphenyl)- 7-(1- ethylpropyl)-1- methyl-1H-benzimidazol-2- amine Hydrochloride ¹H NMR (CDCl₃) δ 0.86 (t, J = 7.4Hz, 6H), 1.70-1.83 (m, 4H), 2.12 (s, 3H), 3.21-3.27 (m, 1H), 3.82 (s,3H), 3.89 s, 3H), 6.93 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 7.03 (s, 1H),7.07-7.11 (m, 1H), 7.35 (s, 1H). MS Calcd.: 415; Found: 416 (M + H). 5

N-(4-Bromo-2- methoxy-6- methylphenyl)- 7-isopropyl-1- methyl-1H-benzimidazol-2- amine ¹H NMR (CDCl₃) δ 1.39 (d, J = 6.9 Hz, 6H), 2.12(s, 3H), 3.82 (s, 3H), 3.86 (s, 1H), 3.93 (s, 3H), 5.87 (m, 1H), 6.92(s, 1H), 7.00-7.10 (m, 3H), 7.36 (m, 1H). MS Calcd.: 387; Found: 388(M + H). 6

7-[bis(4- methoxyphenyl) methyl]-N-(4- chloro-2- methoxy-6-methylphenyl)- 1-methyl-1H- benzimidazol-2- amine ¹H NMR (CDCl₃) δ 2.12(s, 3H), 3.66 (s, 3H), 3.77 (s, 3H), 3.80 (s, 6H), 6.12 (m, 1H), 6.50(d, J = 8.1 Hz ,1H), 6.75- 6.88 (m, 6H), 6.95-7.00 (m, 5H), 7.41 (m,1H). MS Calcd.: 529; Found: 530 (M + H). 7

N-(4-chloro-2- methoxy-6- methylphenyl)- 7-[1-(4- methoxyphenyl)propyl]-1- methyl-1H- benzimidazol-2- amine ¹H NMR (CDCl₃) δ 0.99 (t, J= 7.2 Hz, 3H), 2.00-2.25 (m, 2H), 2.12 (s, 3H), 3.74 (s, 1H), 3.75 (s,3H), 3.77 (s, 3H), 4.47 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H),6.82(d, J = 8.7 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 7.05-7.20 (m, 4H),7.37 (m, 1H). MS Calcd.: 449; Found: 450 (M + H).

Example 8{2-[(4-Bromo-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl}(4-methoxyphenyl)methanone

7-(4-Methoxybenzoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

A solution of 12 mL (6.00 mmol) of 4-methoxymagnesium bromide (0.5Msolution in THF) was diluted with 15 mL of THF and cooled in an icebath. To this solution was slowly added 309 mg (1.50 mmol) of1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-7-carboxylic acid methylester and the reaction was stirred for 24 h at 60° C. The reaction wasquenched with water. The aqueous mixture was extracted withethylacetate. The extract was washed with 1N aqueous hydrochloric acidand brine, dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography eluting with 20-70% ethylacetate/n-hexane to give the title compound (148 mg, 35%).

¹H NMR (DMSO-d₆) δ 3.00 (s, 3H), 3.87 (s, 3H), 6.98 (d, J=8.1 Hz, 1H),7.00-7.15 (m, 3H), 7.19 (d, J=8.1 Hz, 1H), 7.81 (d, J=7.2 Hz, 2H).

MS Calcd.: 282. Found: 283 (M+H).

(2-Chloro-1-methyl-1H-benzimidazol-7-yl)(4-methoxyphenyl)-methanone

A mixture of 145 mg (0.514 mmol) of7-(4-methoxybenzoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one wasdissolved in 1.5 mL of phosphorous oxychloride and heated at 100° C. for18 h. The reaction was allowed to cool to room temperature andconcentrated in vacuo. The residue thus obtained was dissolved in ethylacetate, washed with aqueous sodium bicarbonate, dried over magnesiumsulfate, filtered and concentrated in vacuo to give 124 mg (80%) of thetitle compound, which was used in the next step without furtherpurification.

MS Calcd.: 300. Found: 301 (M+H).

{2-[(4-bromo-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl}(4-methoxyphenyl)methanone

A mixture of 120 mg (0.399 mmol) of(2-chloro-1-methyl-1H-benzimidazol-7-yl)(4-methoxyphenyl)-methanone and216 mg (0.998 mmol) of 4-bromo-2-methoxy-6-methylphenylamine in 0.5 mlof 1-methyl-2-pyrrolidone was heated at 100° C. for 20 h. The reactionwas cooled to room temperature and the residue was dissolved indichloromethane, washed with water, dried over magnesium sulfate,filtered, and concentrated in vacuo. This residue thus obtained waspurified by preparative HPLC to give the title compound as thetrifluoroacetic acid salt. The salt was dissolved in ethyl acetate andwashed with aqueous sodium bicarbonate, dried over magnesium sulfate,filtered and concentrated in vacuo to give 30 mg (16%) of the titlecompound.

¹H NMR (CDCl₃) δ 2.19 (s, 3H), 3.56 (s, 3H), 3.82 (s, 3H), 3.91 (s, 3H),5.94 (m, 1H), 6.94 (d, J=1.8 Hz, 1H), 6.99 (d, J=8.7 Hz, 2H), 7.06 (d,J=1.8 Hz, 1H), 7.10-7.20 (m, 2H), 7.65 (d, J=6.9 Hz, 1H), 7.96 (d, J=8.7Hz, 2H);

MS Calcd.: 481. Found: 482 (M+H).

Example 9N-(4-Bromo-2-methoxy-6-methylphenyl)-4-(1-ethylbutyl)-3-methyl-3H-imidazo[4,5-c]pyridin-2-amine

4-Bromo-3-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one

A solution of 20.0 g (103 mmol)3-methyl-4-nitro-1H-imidazo[4,5-c]pyridin-2(3H)-one in 168 mL 48%hydrobromic acid was heated for 6 h at 135° C. An additional 33 mL of48% hydrobromic acid was added and the reaction was stirred at 135° C.overnight. The reaction was cooled to room temperature and quenched into1675 mL ice water. The resulting slurry was adjusted to pH 9 by theaddition of 125 mL saturated aqueous ammonium hydroxide. The precipitatewas filtered and washed with 200 mL water and dried in a vacuum oven at50° C. overnight to give 17.58 g (75%) of the title product as a lightyellow solids.

¹H NMR (DMSO-d₆) δ 3.54 (3H, s), 7.08 (1H, d, J=4.9 Hz), 7.94 (1H, d,J=4.9 Hz), 11.71 (1H, s).

MS Calcd.: 227. Found: 228 (M+H).

(E)-4-(Hex-3-en-3-yl)-3-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one

A mixture of 0.68 g (3.0 mmol) of4-bromo-3-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one and 0.17 g (0.20mmol) of PdCl₂dppf-dichloromethane complex was dissolved in 12 mL oftoluene and treated with 3.8 mL (7.7 mmol) of 2N sodium carbonate and0.72 g (3.6 mmol) of (Z)-2-(hex-3-en-3-yl)benzo[d][1,3,2]dioxaborole.The resulting mixture was heated to 90° C. for 5 h, partitioned betweenwater and ethyl acetate, filtered to remove fine precipitates andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated invacuo. The brown oil thus obtained was purified by flash chromatographyeluting with a 25% methanol/dichloromethane mixture to give 0.40 g (58%)of the title compound as a cream colored solid.

¹H NMR (CDCl₃) δ 1.01 (3H, t, J=7.6 Hz), 1.10 (3H, t, J=7.6 Hz),2.29-2.36 (2H, m), 2.66 (2H, q, J=7.4 Hz), 3.46 (3H, s), 5.46 (1H, t,J=7.2 Hz), 6.98 (1H, d, J=5.3 Hz), 8.28 (1H, d, J=5.1 Hz), 10.83 (1H, brs).

MS Calcd.: 231. Found: 232 (M+H).

4-(Hexan-3-yl)-3-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one

To a solution of 0.36 g (1.6 mmol) of(E)-4-(hex-3-en-3-yl)-3-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one in 30mL of ethanol was added 0.99 g (10 mol % Pd) of palladium on carbon (50%wet, Degussa type). The reaction was kept under a hydrogen atmospherevia a balloon and stirred at room temperature for 6 h. The catalyst wasremoved via filtration and the filtrate was concentrated in vacuo togive 0.33 g (91%) of the title compound as a grey oil that solidifiedupon standing.

¹H NMR (CDCl₃) δ 0.81 (3H, t, J=7.4 Hz), 0.87 (3H, t, J=7.4 Hz),1.12-1.29 (2H, m), 1.66-1.82 (2H, m), 1.88-1.99 (2H, m), 3.21-3.28 (1H,m), 3.67 (3H, s), 6.94 (1H, d, J=5.2 Hz), 8.31 (1H, d, J=5.2 Hz), 10.25(1H, br s).

MS Calcd.: 233. Found: 234 (M+H).

2-Chloro-4-(hexan-3-yl)-3-methyl-3H-imidazo[4,5-c]pyridine

Prepared from 4-(hexan-3-yl)-3-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-oneaccording to the method described previously for2-chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazole in 68% isolatedyield.

¹H NMR (CDCl₃) δ 0.80 (3H, t, J=7.4 Hz), 0.86 (3H, t, J=7.4 Hz),1.06-1.31 (2H, m), 1.68-1.93 (2H, m), 1.95-2.04 (2H, m), 3.30-3.37 (1H,m), 4.05 (3H, s), 7.43 (1H, d, J=5.4 Hz), 8.43 (1H, d, J=5.4 Hz).

MS Calcd.: 251. Found: 252 (M+H).

N-(4-bromo-2-methoxy-6-methylphenyl)-4-(1-ethylbutyl)-3-methyl-3H-imidazo[4,5-c]pyridin-2-amine

Prepared from according to the method described previously for2-chloro-4-(hexan-3-yl)-3-methyl-3H-imidazo[4,5-c]pyridine in 47%isolated yield.

¹H NMR (CDCl₃) δ 0.84 (3H, t, J=7.4 Hz), 0.88 (3H, t, J=7.4 Hz),1.14-1.32 (2H, m), 1.68-1.84 (2H, m), 1.93-2.02 (2H, m), 2.18 (3H, s),3.24-3.31 (1H, m), 3.82 (3H, s), 3.90 (3H, s), 5.98 (1H, br s), 6.94(1H, s), 7.06 (1H, s), 7.23 (1H, d, J=4.5 Hz), 8.29 (1H, d, J=5.3 Hz).

MS Calcd.: 430. Found: 431 (M+H).

Compounds described below were prepared in a similar method.

TABLE 2 Example Structure Name Physical Data 10

N-(4-bromo-2- methoxy-6- methylphpenyl)-4 [(1E)-1-ethylbut-1-enyl]-3-methyl- 3H-imidazo[4,5- c]pyridin-2-amine ¹H NMR (CDCl₃) δ1.04 (3H, t, J = 7.5 Hz), 1.12 (3H, t, J = 7.5 Hz), 2.22 (3H, s), 2.35(2H, m), 2.71 (2H, q, J = 7.5 Hz), 3.71 (3H, s), 5.53 (1H, t, J = 7.5Hz), 5.97 (1H, m), 6.94 (1H, d, J = 1.8 Hz), 7.07 (1H, d, J = 1.8 Hz),7.28 (1H, d, J = 5.4 Hz), 8.25 (1H, d, J = 5.4 Hz). MS Calcd.: 428;Found: 429 (M + H). 11

N-(4-chloro-2- methoxy-6- methylphenyl)-7- (1-ethylbutyl-1- methyl-1H-imidazo[4,5- c]pyridin-2-amine ¹H NMR (CDCl₃) δ 0.90 (3H, t, J = 7.3 Hz)0.89 (3H, t, J = 7.4 Hz) 1.23-1.36 (2H, m) 1.73-1.90 (4H, m) 2.18 (3H,s) 3.21-3.31 (1H, m) 3.83 (3H, s) 3.90 (3H, s) 5.93 (1H, s) 6.81 (1H, d,J = 2.2 Hz) 6.92 (1H, d, J = 1.7 Hz) 8.17 (1H, s) 8.62 (1H, s) MSCalcd.: 386; Found: 387 (M + H).

Example 124-[2-[(2,4-Dimethylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazol-7-yl]heptan-4-ol

Methyl-2-chloro-3-nitrobenzoate

A slurry of 20 g (99 mmol) of 2-chloro-3-nitrobenzoic acid in 800 mLdichloromethane was cooled in an ice bath. Dimethylformamide (0.40 ml)was added to the reaction mixture followed by dropwise addition of 13.85g (109 mmol) of oxalyl chloride. The reaction was allowed to warm toroom temperature and was stirred for 6 h. Methanol (200 mL) was addeddropwise and the reaction was stirred overnight. The solvent wasevaporated in vacuo. The residue was triturated with n-hexane. Theresulting solid was collected by filtration, washed with hexane anddried in vacuo to give 21.0 g (98%) of the title compound.

¹H NMR (CDCl₃) δ 3.98 (3H, s), 7.49 (1H, t, J=8.4 Hz), 7.84 (1H, dd,J=1.8, 8.4 Hz), 7.96 (1H, dd, J=1.8, 8.4 Hz).

Methyl 2-[(2-hydroxyethyl)amino]-3-nitrobenzoate

To a solution of 4.70 g (21.9 mmol) of methyl 2-chloro-3-nitrobenzoatein 300 mL of THF was added dropwise 300 mL of 2-ethanolamine (80 mmol)and the mixture was refluxed over night. The reaction was concentratedto dryness, dissolved in ethyl acetate, and washed aqueous sodiumhydrogen carbonate and water. The organics were dried over magnesiumsulfate, filtered, and concentrated in vacuo to give 5.00 g (20.8 mmol,95%) of the title compound.

¹H NMR (CDCl₃) δ 1.68 (1H, br), 3.12 (2H, dd, J=4.8, 10.2 Hz), 3.85 (2H,t, J=4.8 Hz), 3.92 (1H, s), 6.69 (1H, t, J=8.1 Hz), 7.96 (1H, dd, J=1.8,8.1 Hz), 8.09 (1H, dd, J=1.8, 8.1 Hz), 8.72 (1H, br).

MS Calcd.: 240. Found: 241 (M+H).

9-Nitro-2,3-dihydro-4,1-benzoxazepin-5(1H)-one

To a solution of 2.00 g (8.32 mmol) of methyl2-[(2-hydroxyethyl)amino]-3-nitrobenzoate in 150 mL of THF was addeddropwise 6N HCl (100 mL) at 0° C. and the mixture was stirred for 30min. The reaction mixture was refluxed for 16 h. After being cooled toroom temperature, the mixture was diluted with water (150 ml), andconcentrated in vacuo. The residue was dissolved in ethyl acetate andwashed with aqueous sodium hydrogen sulfate and water. The organics wasdried over magnesium sulfate, filtered, and concentrated in vacuo togive 1.03 g (5.00 mmol, 60%) of the title compound.

¹H NMR (CDCl₃) δ: 3.91-3.95 (2H, m), 4.58-4.61 (2H, m), 6.79 (1H, t;J=8.4 Hz), 8.19 (1H, dd, J=1.8, 8.4 Hz), 8.43 (1H, dd, J=1.8, 8.4 Hz),8.96 (1H, br).

MS Calcd.: 208. Found: 209 (M+H).

9-Amino-2,3-dihydro-4,1-benzoxazepin-5(1H)-one

A solution of 500 mg (2.42 mmol) of9-nitro-2,3-dihydro-4,1-benzoxazepin-5(1H)-one in 500 mL of methanol wasinerted with nitrogen. To this solution was added 100 mg of 10%palladium on carbon (50% wet) and the reaction was purged with hydrogenand stirred under balloon pressure hydrogen for 6 h. The catalyst wasremoved by filtration and the filtrate was concentrated in vacuo to give430 mg (99%) of the title compound.

¹H NMR (CD₃OD) δ: 3.00-3.03 (2H, m), 3.77-3.80 (2H, m), 5.95 (1H, t,J=8.4 Hz), 6.25 (1H, dd, J=1.5, 8.4 Hz), 6.56 (1H, dd, J=1.5, 8.4 Hz).

MS Calcd.: 178. Found: 179 (M+H).

4,5-Dihydro-7H-imidazo[4,5,1-jk][4,1]benzoxazepine-2,7(1H)-dione

To a solution of 200 mg (1.13 mmol) of9-amino-2,3-dihydro-4,1-benzoxazepin-5(1H)-one in 20 mL of THF was added280 mg (2 mmol) of 1,1′-carbonyldiimidazole and the reaction mixture wasstirred overnight at room temperature. The reaction mixture was heatedat 50° C. for 4 h and allowed to cool to room temperature. The reactionwas concentrated in vacuo and the residue was dissolved in a mixture ofethyl acetate/n-hexane (1:1) and washed with water. The organics weredried over sodium sulfate, filtered, and concentrated in vacuo to give286 mg (1.40 mmol, 70%) of the title compound.

¹H NMR (CD₃OD) δ: 4.25-4.27 (2H, m), 4.75-4.77 (2H, m), 7.23 (1H, t,J=8.4 Hz), 7.37 (1H, dd, J=1.2, 8.4 Hz), 7.78 (1H, dd, J=1.5, 8.4 Hz).

MS Calcd.: 204. Found: 205 (M+H).

2-Chloro-4,5-dihydro-7H-imidaz[4,5,1-jk][4,1]benzoxazepin-7-one

4,5-Dihydro-7H-imidazo[4,5,1-jk][4,1]benzoxazepine-2,7(1H)-dione (1.00g, 4.89 mmol) was dissolved in 15 mL of phosphorous oxychloride andheated at 110° C. for 6 h. The reaction allowed to cool to roomtemperature, poured into water with an ice, and stirred for 1 h. Theaqueous solution was extracted with ethyl acetate. The extract waswashed with aqueous sodium bicarbonate, dried over magnesium sulfate,filtered and concentrated in vacuo to give 1.06 g (98%) of the titlecompound, which was used in the next reaction without furtherpurification.

MS Calcd.: 222. Found: 223 (M+H).

2-[(2,4-Dimethylphenyl)amino]-4,5-dihydro-7H-imidazo[4,5,1-jk][4,1]benzoxazepin-7-one

A mixture of2-chloro-4,5-dihydro-7H-imidaz[4,5,1-jk][4,1]benzoxazepin-7-one 1.06 g(4.77 mmol) and 2,4-methylaniline 1.73 g (14.3 mmol) in 0.1 ml ofN-methyl-2-pyrrolidone was heated at 100° C. overnight. The reaction wascooled to room temperature and the residue was dissolved indichloromethane, washed with sodium bicarbonate and water, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue wastriturated with ethyl acetate/n-hexane (1:1) to give 0.96 g (66%) of thetitle compound.

¹H NMR (CDCl₃) δ: 2.14 (3H, s), 2.22 (3H, s), 4.35-4.37 (2H, m),4.78-4.80 (2H, m), 5.98 (1H, br), 6.59 (1H, d, J=7.2 Hz), 6.84 (1H, d,J=7.2 Hz), 6.87 (1H, s), 7.24 (1H, t, J=7.8 Hz), 7.72 (1H, d, J=7.8 Hz),7.86 (1H, d, J=7.8 Hz).

MS Calcd.: 307. Found: 308 (M+H).

4-[2-[(2,4-Dimethylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazol-7-yl]heptan-4-ol

To a refluxing solution of 30 mL of n-propylmagnesium bromide (27% intetrahydrofuran) was added 500 mg (1.63 mmol) of2-[(2,4-dimethylphenyl)amino]-4,5-dihydro-7H-imidazo[4,5,1-jk][4,1]benzoxazepin-7-oneand the mixture was refluxed for 1 h. The reaction mixture was cooled toroom temperature and diluted with 50 mL of water and neutralization with1N HCl. The aqueous solution was extracted with ethyl acetate. Theextract was dried over magnesium sulfate, filtered, and concentrated invacuo. The residue thus obtained was purified by preparative HPLC togive the title compound as the trifluoroacetic acid salt. The salt wasdissolved in ethyl acetate and washed with aqueous sodium bicarbonate,dried over magnesium sulfate, filtered and concentrated in vacuo to give161 mg (0.41 mmol, 25%) of the title compound.

¹H NMR (CDCl₃) δ: 0.92 (6H, t, J=7.5 Hz), 1.23-1.41 (4H, m), 1.81-1.91(2H, m), 1.98-2.09 (2H, m), 2.13 (3H, s), 2.22 (3H, s), 4.21 (2H, t,J=4.8 Hz), 4.45 (2H, t, J=4.8 Hz), 6.59 (1H, d, J=7.2 Hz), 6.84 (1H, d,J=7.2 Hz), 6.87 (1H, s), 6.83 (1H, d, J=8.1 Hz), 7.03 (1H, t, J=8.1 Hz),7.41 (1H, d, J=8.1 Hz).

MS Calcd.: 395. Found: 396 (M+H).

Compounds described below were prepared in a similar method.

TABLE 3 Example Structure Name Physical Data 13

4-[2-[(4-chloro- 2-methoxy-6- methylphenyl) amino]-1-(2- hydroxyethyl)-1H-benzimidazol- 7-yl]heptan-4-ol ¹H NMR (CDCl₃) δ 0.92 (6H, t, J = 7.5Hz), 1.23-1.41 (4H, m), 1.81-1.91 (2H, m), 1.98-2.09 (2H, m), 2.21 (3H,s), 3.81 (3H, s), 4.21 (2H, t, J = 4.8 Hz), 4.45 (2H, t, J = 4.8 Hz),6.82 (1H, d, J = 2.1 Hz), 6.92 (1H, d, J = 2.1 Hz), 6.83 (1H, d, J = 8.1Hz), 7.03 (1H, t, J = 8.1 Hz), 7.41 (1H, d, J = 8.1 Hz). MS Calcd.: 445;Found: 446 (M + H).

Example 142-[2-[(2,4-Dimethylphenyl)amino]-7-(1-propylbutyl)-1H-benzimidazol-1-yl]ethanol

A solution of 100 mg (0.25 mmol) of9-nitro-2,3-dihydro-4,1-benzoxazepin-5(1H)-one in 3 mL of ethanol wasinerted with nitrogen. To this solution was added an ethanol solution ofRaney nickel and the reaction was purged with hydrogen and stirred underballoon pressure hydrogen for 6 h. The catalyst was removed byfiltration and the filtrate was concentrated in vacuo. The residue thusobtained was purified by preparative HPLC to give the title compound asthe trifluoroacetic acid salt. The salt was dissolved in ethyl acetateand washed with aqueous sodium bicarbonate, dried over magnesiumsulfate, filtered and concentrated in vacuo to give 27 mg (0.07 mmol,28%) of the title compound.

¹H NMR (CDCl₃) δ: 0.92 (6H, t, J=7.5 Hz), 1.22-1.41 (4H, m), 1.79-1.89(2H, m), 1.98-2.09 (2H, m), 2.12 (3H, s), 2.22 (3H, s), 2.87 (1H, q,J=7.2 Hz), 4.21 (2H, t, J=4.8 Hz), 4.45 (2H, t, J=4.8 Hz), 6.59 (1H, d,J=7.2 Hz), 6.84 (1H, d, J=7.2 Hz), 6.87 (1H, s), 6.85 (1H, d, J=8.1 Hz),7.05 (1H, t, J=8.1 Hz), 7.45 (1H, d, J=8.1 Hz).

MS Calcd.: 379. Found: 380 (M+H).

Example 15N-(4-Chloro-2-methoxy-6-methylphenyl)-7-(2-ethylphenyl)-1-methyl-1H-benzimidazol-2-amine

7-Bromo-2-chloro-1-methyl-1H-benzimidazole

7-Bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (2.20 g, 9.69 mmol)was dissolved in 30 mL of phosphorous oxychloride and the mixture washeated at 110° C. for 2 days. The reaction allowed to cool to roomtemperature, poured into water with an ice, and stirred for 1 h. Theaqueous solution was extracted with ethyl acetate. The extract waswashed with aqueous sodium bicarbonate, dried over magnesium sulfate,filtered and concentrated in vacuo to give 2.32 g of the title compound,which was used in the next reaction without further purification.

MS Calcd.: 243. Found: 244 (M+H).

7-Bromo-N-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-1H-benzimidazol-2-amine

To a mixture of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 2.32g (9.69 mmol) and 4-chloro-2-methoxy-6-methylaniline 4.98 g (29.1 mmol)in 0.5 mL of N-methyl-2-pyrrolidone was heated at 110° C. for 2 days.The reaction was cooled to room temperature and diluted withdichloromethane. The mixture was washed with sodium bicarbonate andwater, dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was triturated with ethyl acetate/hexane (1:1) togive 3.13 g (8.23 mmol, 85%) of the title compound.

¹H NMR (CDCl₃) δ: 2.17 (3H, s), 3.82 (3H, s), 4.04 (3H, s), 6.80 (1H, d,J=2.4 Hz), 6.89 (1H, d, J=2.4 Hz), 6.56 (1H, t, J=8.1 Hz), 7.21 (1H, d,J=8.1 Hz), 7.42 (1H, d, J=8.1 Hz).

MS Calcd.: 379. Found: 380 (M+H).

N-(4-Chloro-2-methoxy-6-methylphenyl)-7-(2-ethylphenyl)-1-methyl-1H-benzimidazol-2-aminetrifluoroacetic acid salt

To a mixture of 25 mg (65.6 μmol) of7-bromo-N-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-1H-benzimidazol-2-amine,11.8 mg (78.7 μmol) of 2-ethylphenylboronic acid, 12.0 mg (13.1 μmol) oftris(dibenzylideneacetone)dipalladium and 12.5 mg (26.2 μmol) of2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl in 1 mL of1,2-dimethoxyethane was added 131 μl of 1M aqueous potassium phosphatetribasic solution. The reaction mixture was heated by microwaveirradiation at 130° C. for 10 min, and allowed to cool to roomtemperature. The reaction mixture was diluted with dichloromethane andwater, separated with a filter tube (made by Wattmann) and concentratedin vacuo. The residue was purified by preparative HPLC to give 2.5 mg(9.8%) of the title compound as a trifluoroacetic acid salt.

¹H NMR (CDCl₃) δ: 1.05 (3H, t, J=7.5 Hz), 2.17 (3H, s), 2.40-2.54 (2H,m), 3.07 (3H, s), 3.80 (3H, s), 6.78 (1H, d, J=2.4 Hz), 6.89 (1H, d,J=2.4 Hz), 6.89 (1H, d, J=7.8 Hz), 7.13 (1H, t, J=7.8 Hz), 7.23-7.41(4H, m), 7.51 (1H, d, J=7.8 Hz).

MS Calcd.: 405. Found: 406 (M+H).

Example 16-60

Examples 16-54 in Table 4 were prepared as trifluoroacetic acid salt andexamples 55-60 were prepared as free base in the similar methoddescribed in Example 15.

TABLE 4 Example Structure Name Physical Data 16

N-(4-chloro-2- methoxy-6- methylphenyl)-1- methyl-7-(2- methylphenyl)-1H-benzimidazol- 2-amine MS Calcd.: 391; Found: 392 (M + H). 17

N-(4-chloro-2- methoxy-6- methylphenyl)-7- (2,3- dimethylphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 405; Found: 406 (M + H).18

N-(4-chloro-2- methoxy-6- methylphenyl)-7- (2,4- dimethylphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 405; Found: 406 (M + H).19

N-(4-chloro-2- methoxy-6- methylphenyl)-7- (3-chloro-2- methylphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 425; Found: 426 (M + H). 20

N-(4-chloro-2- methoxy-6- methylphenyl)-7- (3,5- dimethylphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 405; Found: 406 (M + H).21

N-(4-chloro-2- methoxy-6- methylphenyl)-7- mesityl-1- methyl-1H-benzimidazol-2- amine MS Calcd.: 419; Found: 420 (M + H). 22

N-(4-chloro-2- methoxy-6- methylphenyl)-1- methyl-7-[2-(trifluoromethyl) phenyl]-1H- benzimidazol-2- amine MS Calcd.: 445;Found: 446 (M + H). 23

1-(2-{2-[(4- chloro-2- methoxy-6- methylphenyl) amino]-1-methyl-1H-benzimidazol-7- yl}phenyl) ethanone MS Calcd.: 419; Found: 420 (M +H). 24

7-(5-amino-2- methylphenyl)-N- (4-chloro-2- methoxy-6- methylphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 406; Found: 407 (M + H). 25

N-(4-chloro-2- methoxy-6- methylphenyl)-7- (3-methoxyphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 407; Found: 408 (M + H).26

N-(4-chloro-2- methoxy-6- methylphenyl)-7-(2- isopropoxyphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 435; Found: 436 (M + H).27

N-(4-chloro-2- methoxy-6- methylphenyl)-7-(2- ethoxyphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 421; Found: 422 (M + H). 28

N-(4-chloro-2- methoxy-6- methylphenyl)-7- (2-chloro-6- methoxyphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 441; Found: 442 (M + H).29

N-(4-chloro-2- methoxy-6- methylphenyl)-7- (2,4- dimethoxyphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 437; Found: 438 (M + H).30

2-{2-[(4-chloro- 2-methoxy-6- methylphenyl) amino]-1-methyl-1H-benzimidazol-7- yl}phenol MS Calcd.: 393; Found: 394 (M + H). 31

7-[3- (benzyloxy)phenyl]- N-(4-chloro- 2-methoxy-6- methylphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 483; Found: 484 (M + H). 32

N-(4-chloro-2- methoxy-6- methylphenyl)-7-(2- chlorophenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 411; Found: 412 (M + H). 33

N-(4-chloro-2- methoxy-6- methylphenyl)-7- (2,4- dichlorophenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 445; Found: 446 (M + H).34

N-(4-chloro-2- methoxy-6- methylphenyl)-7-(4- methoxyphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 407; Found: 408 (M + H).35

N-(4-chloro-2- methoxy-6- methylphenyl)-7- (2-ethoxy-5- methylphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 435; Found: 436 (M + H). 36

7-(1,1′- biphenyl-2-yl)- N-(4-chloro-2- methoxy-6- methylphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 453; Found: 454 (M + H). 37

N-(2-{2-[(4- chloro-2- methoxy-6- methylphenyl) amino]-1-methyl-1H-benzimidazol-7- yl}phenyl) methanesulfonamide MS Calcd.: 470; Found:471 (M + H). 38

N-(4-chloro-2- methoxy-6- methylphenyl)-1- methyl-7-(2- nitrophenyl)-1H-benzimidazol-2- amide MS Calcd.: 422; Found: 423 (M + H). 39

7-(3- aminophenyl)-N- (4-chloro-2- methoxy-6- methylphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 392; Found: 393 (M + H). 40

7-(1-benzothien- 2-yl)-N-(4- chloro-2- methoxy-6- methylphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 433; Found: 434 (M + H). 41

7-(1,1′- biphenyl-3-yl)- N-(4-chloro-2- methoxy-6- methylphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 453; Found: 454 (M + H). 42

N-(4-chloro-2- methoxy-6- methylphenyl)-1- methyl-7-(1- methyl-1H-pyrazol-4-yl)- 1H-benzimidazol- 2-amine MS Calcd.: 381; Found: 382 (M +H). 43

3-(3-{2-[(4- chloro-2- methoxy-6- methylphenyl) amino]-1-methyl-1H-benzimidazol-7- yl}phenyl)propan- 1-ol MS Calcd.: 435; Found: 436 (M +H). 44

N-(4-chloro-2- methoxy-6- methylphenyl)-7- [(E)-2- cyclohexylvinyl]-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 409; Found: 410 (M + H).45

N-(4-chloro-2- methoxy-6- methylphenyl)-1- methyl-7-[(1E)-prop-1-enyl]-1H- benzimidazol-2- amine MS Calcd.: 341; Found: 342 (M +H). 46

1-(5-{2-[(4- chloro-2- methoxy-6- methylphenyl) amino]-1-methyl-1H-benzimidazol-7- yl}thien-2- yl)ethanone MS Calcd.: 425; Found: 426(M + H). 47

N-(4-chloro-2- methoxy-6- methylphenyl)-1- methyl-7-[(E)-2-phenylvinyl]-1H- benzimidazol-2- amine MS Calcd.: 403; Found: 404 (M +H). 48

N-(4-chloro-2- methoxy-6- methylphenyl)-1- methyl-7-(1- naphthyl)-1H-benzimidazol-2- amine MS Calcd.: 427; Found: 428 (M + H). 49

N-(4-chloro-2- methoxy-6- methylphenyl)-1- methyl-7-phenyl-1H-benzimidazol- 2-amine MS Calcd.: 377; Found: 378 (M + H). 50

N-(4-chloro-2- methoxy-6- methylphenyl)-7- (4-chloro-2- methylphenyl)-1-methyl-1H- benzimidazol-2- amine MS Calcd.: 425; Found: 426 (M + H). 51

N-(4-chloro-2- methoxy-6- methylphenyl)-7- (4-methoxy-2-methylphenyl)-1- methyl-1H- benzimidazol-2- amine MS Calcd.: 421; Found:422 (M + H). 52

N-(4-chloro-2- methoxy-6- methylphenyl)-1- methyl-7-(2- naphthyl)-1H-benzimidazol-2- amine MS Calcd.: 427; Found: 428 (M + H). 53

N-(3-{2-[(4- chloro-2- methoxy-6- methylphenyl) amino]-1-methyl-1H-benzimidazol-7- yl}phenyl)acetamide MS Calcd.: 434; Found: 435 (M +H). 54

2-{2-[(4-chloro- 2-methoxy-6- methylphenyl) amino]-1-methyl-1H-benzimidazol-7- yl}benzaldehyde MS Calcd.: 405; Found: 406 (M + H).55

N-(4-chloro-2- methoxy-6- methylphenyl)-7-(2- isopropylphenyl)-1-methyl-1H- benzimidazol-2- amine ¹H NMR (CDCl₃) δ 1.11 (3H, d, J = 6.9Hz), 1.15 (3H, d, J = 6.9 Hz), 2.18 (3H, s), 2.80-2.95 (1H, m), 3.09(3H, s), 3.81 (3H, s), 5.79 (1H, s), 6.78 (1H, d, J = 2.1 Hz), 6.87-6.89(2H, m), 7.12 1H, t, J = 7.5 Hz), 7.20-7.30 (2H, m), 7.42-7.43 (2H, m),7.52 (1H, d, J = 7.5 Hz). MS Calcd.: 419; Found: 420 (M + H). 56

N-(4-chloro-2- methoxy-6- methylphenyl)-7-(2- methoxyphenyl-1-methyl-1H- benzimidazol-2- amine ¹H NMR (DMSO-d₆) δ 2.09 (3H, s), 3.15(3H, s), 3.74 (3H, s), 3.76 (3H, s), 6.68 (1H, d, J = 7.8 Hz), 6.96-7.14(6H, m), 7.28 (1H, d, J = 7.8 Hz), 7.44 (1H, t, J = 7.8 Hz), 7.90 (1H,s). MS Calcd.: 407; Found: 408 (M + H). 57

N-2′,3- dimethoxy-5- methyl-1,1′- biphenyl-4-yl)-7- (2-methoxyphenyl)-1-methyl-1H- benzimidazol-2- amine ¹H NMR (DMSO-d₆) δ 2.13 (3H, s), 3.15(3H, s), 3.75 (6H, s), 3.81 (3H, s), 6.67 (1H, dd, J = 7.5, 1.2 Hz),6.94- 7.15 (8H, m), 7.27-7.47 (4H, m), 7.86 (1H, s). MS Calcd.: 479;Found: 480 (M + H). 58

N-(4-chloro-2- methoxy-6- methylphenyl)-7-(2- methoxypyridin-3-yl)-1-methyl- 1H-benzimidazol- 2-amine ¹H NMR (CDCl₃-CD₃OD) δ 2.19(3H, s), 3.27 (3H, s), 3.81 (3H, s), 3.94 (3H, s), 6.84-6.90 (3H, m),7.07-7.14 (2H, m), 7.33 (1H, d, J = 8.4 Hz), 7.70 (1H, d, J = 7.5, 1.8Hz), 8.23 (1H, dd, J = 5.4, 1.8 Hz). MS Calcd.: 408; Found: 409 (M + H).59

N-(4-chloro-2- methoxy-6- methylphenyl)-1- methyl-7-(3- methyl-2-thienyl)-1H- benzimidazol-2- amine ¹H NMR (CDCl₃-CD₃OD) δ 2.07 (3H, s),2.17 (3H, s), 3.21 (3H, s), 3.81 (3H, s), 5.81 (1H, s), 6.78 (1H, d, J =2.1 Hz), 6.88-6.91 (2H, m), 7.05-7.14 (2H, m), 7.22 (1H, d, J = 3.0 Hz),7.51 (1H, d, J = 8.1 Hz). MS Calcd.: 397; Found: 398 (M + H). 60

N-(4-chloro-2- methoxy-6- methylphenyl)-7- (2-ethylphenyl)- 1-methyl-1H-imidazo[4,5- c]pyridin-2- amine ¹H NMR (CDCl₃) δ 1.07 (3H, t, J = 7.6Hz), 2.23 (3H, s), 2.40-2.59 (2H, m), 3.17 (3H, s), 3.82 (3H, s), 5.88(1H, s), 6.81 (1H, d, J = 1.5 Hz), 6.93 (1H, d, J = 1.5 Hz), 7.20-7.51(4H, m), 8.09 (1H, s), 8.77 (1H, s). MS Calcd.: 406; Found: 407 (M + H).

Example 61N-(4-Bromo-2-methoxy-6-methylphenyl)-7-(2-ethylphenyl)-1-methyl-1H-benzimidazol-2-amine

7-(2-Ethylphenyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

A mixture of 280 mg (1.23 mmol) of7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 222 mg (1.48 mmol)of 2-ethylphenylboronic acid, 113 mg (0.0123 mmol) oftris(dibenzylideneacetone)dipalladium, 29 mg (0.0615 mmol) of X-Phos and522 mg (2.46 mmol) of potassium phosphate in 9 mL of toluene was stirredat 100° C. for 4 hours. After cooling, the reaction mixture was dilutedwith water and ethyl acetate and passed through celite. The filtrate wasextracted with ethyl acetate (X2). The combined organic layer was washedwith brine (X1), dried over sodium sulfate and concentrated in vacuo.The residue was purified by silica gel column chromatography elutingwith a 25-65% ethylacetate/n-hexane gradient mixture to give 200 mg(64%) of the title compound.

¹H NMR (CDCl₃) δ 1.04 (3H, t, J=7.7 Hz), 2.34-2.52 (2H, m), 2.84 (3H,s), 6.86-6.98 (2H, m), 7.05-7.08 (2H, m), 7.18-7.39 (3H, m), 8.58 (1H,br s).

MS Calcd.: 252. Found: 253 (M+H).

2-Chloro-7-(2-ethylphenyl)-1-methyl-1H-benzimidazole

A mixture of 190 mg (0.753 mmol) of7-(2-ethylphenyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and 1.5 mLof phosphorus oxychloride was stirred at 80° C. for 5 hours. Aftercooling, the reaction mixture was poured into ice and neutralized by 12N sodium hydroxide. The aqueous suspension was extracted with ethylacetate (X2). The combined organic layer was washed with brine (X1),dried over sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with a 3-10%ethylacetate/n-hexane gradient mixture to give 123 mg (60%) of the titlecompound.

¹H NMR (CDCl₃) δ 1.02 (3H, t, J=7.5 Hz), 2.30-2.48 (2H, m), 3.19 (3H,s), 7.05-7.15 (1H, m), 7.26-7.45 (5H, m), 7.60 (1H, m).

MS Calcd.: 270, 272. Found: 271, 273 (M+H).

N-(4-Bromo-2-methoxy-6-methylphenyl)-7-(2-ethylphenyl)-1-methyl-1H-benzimidazol-2-amine

A mixture of 100 mg (0.369 mmol) of2-chloro-7-(2-ethylphenyl)-1-methyl-1H-benzimidazole and 239 mg (1.11mmol) of 4-bromo-2-methoxy-6-methylaniline was stirred at 120° C. for 15hours. After cooling, the reaction mixture was neutralized by saturatedaqueous sodium hydrogen carbonate, followed by addition of ethylacetate. The resulting crystals were collected by filtration and washedwith water and ethyl acetate, and suspended in hot ethyl acetate. Aftercooling to room temperature, the crystals were collected by filtrationand washed with ethyl acetate and a 50% dimethylsulfoxide/methanolmixture to give 90 mg (54%) of the title compound.

¹H NMR (CDCl₃) δ 1.05 (3H, t, J=7.4 Hz), 2.16 (3H, s), 2.40-2.55 (2H,m), 3.09 (3H, s), 3.81 (3H, s), 5.79 (1H, br s), 6.88-6.92 (2H, m), 7.04(1H, d, J=1.5 Hz), 7.12 (1H, t, J=7.8 Hz), 7.26-7.41 (4H, m), 7.52 (1H,d, J=7.8 Hz).

MS Calcd.: 449, 451. Found: 450, 452 (M+H).

Compounds described below were prepared in a similar method.

TABLE 5 Example Structure Name Physical Data 62

N-(4-bromo-2- methoxy-6- methylphenyl)- 1-methyl-7-(3- methylphenyl)-1H-benzimidazol-2- amine ¹H NMR (CDCl₃) δ 2.16 (3H, s), 2.43 (3H, s), 3.25(3H, s), 3.82 (3H, s), 5.80 (1H, br s), 6.93-7.53 (9H, m). MS Calcd.:435, 437; Found: 436, 438 (M + H). 63

N-(4-bromo-2- methoxy-6- methylphenyl)- 1-methyl-7-(4- methylphenyl)-1H-benzimidazol-2- amine ¹H NMR (CDCl₃) δ 2.16 (3H, s), 2.44 (3H, s), 3.26(3H, s), 3.82 (3H, s), 5.83 (1H, s), 6.92 (1H, d, J = 1.0 Hz), 6.94 (1H,d, J = 7.5 Hz), 7.04 (1H, d, J = 1.0 Hz), 7.13 (1H, t, J = 7.5 Hz), 7.25(2H, d, J = 7.8 Hz), 7.35 (2H, d, J = 7.8 Hz), 7.50 (1H, d, J = 7.5 Hz).MS Calcd.: 435, 437; Found: 436, 438 (M + H).

Example 64N-(4-Chloro-2-methoxy-6-methylphenyl)-1-methyl-7-{2-[(methylamino)methyl]phenyl}-1H-benzimidazol-2-amine

A mixture of 33 mg (0.0813 mmol) of2-[2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl]benzaldehyde,0.033 mL (0.325 mmol) of 40% methanol solution of methyl amine and 1 mLof ethanol was refluxed for 4 hours. After cooling, 9.2 mg (0.244 mmol)of sodium borohydride was added. The mixture was stirred at roomtemperature for 4 hours, and 15 mg (0.407 mmol) of sodium borohydridewas added. After stirring at room temperature for 15 hours, the reactionmixture was diluted with water and extracted with ethyl acetate (X2).The combined organic layer was washed with brine (X1), dried over sodiumsulfate and concentrated in vacuo. The residue was purified bypreparative HPLC and basic silica gel column chromatography eluting witha 50-100% ethylacetate/n-hexane gradient mixture to give 5 mg (17%) ofthe title compound.

¹H NMR (CDCl₃) δ 2.18 (3H, s), 2.27 (3H, s), 3.08 (3H, s), 3.57 (2H, s),3.81 (3H, s), 6.79 (1H, s), 6.87-6.89 (2H, m), 7.10-7.15 (1H, m),7.33-7.53 (5H, m).

Example 65N-(4-Bromo-2-methoxy-6-methylphenyl)-1-methyl-7-(3-methyl-1H-pyrazol-1-yl)-1H-benzimidazol-2-amine

1-Methyl-7-(3-methyl-1H-pyrazol-1-yl)-1,3-dihydro-2H-benzimidazol-2-one

A suspension of 50 mg (0.220 mmol) of7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 0.035 mL (0.440mmol) of 3-methylpyrazole, 42 mg (0.0220 mmol) of copper(I) iodide and61 mg (0.440 mmol) of potassium carbonate in 1 mL of1-methyl-2-pyrrolidinone was stirred by microwave irradiation at 190° C.for 2 hours. After cooling, the reaction mixture was diluted with waterand extracted with ethyl acetate (X2). The combined organic layer waswashed with brine (X1), dried over sodium sulfate and concentrated invacuo. The residue was purified by silica gel column chromatographyeluting with a 25% ethylacetate/n-hexane mixture to give 57 mg of amixture containing the title compound.

¹H NMR (CDCl₃) δ 2.34 (3H, s), 2.98 (3H, s), 6.26 (1H, d, J=2.2 Hz),6.97-7.18 (3H, m), 7.57 (1H, d, J=2.2 Hz), 9.60 (1H, br s).

MS Calcd.: 228. Found: 229 (M+H).

N-(4-Bromo-2-methoxy-6-methylphenyl)-1-methyl-7-(3-methyl-1H-pyrazol-1-yl)-1H-benzimidazol-2-amine

A mixture of 17 mg (0.0745 mmol) of1-methyl-7-(3-methyl-1H-pyrazol-1-yl)-1,3-dihydro-2H-benzimidazol-2-onein 0.5 mL of phosphorus oxychloride was stirred at 80° C. for 5 days.After cooling, phosphorus oxychloride was evaporated in vacuo. Theresidue was neutralized by 12 N aqueous sodium hydroxide. The aqueoussuspension was extracted with ethyl acetate (X2). The combined organiclayer was washed with water (X1) and brine (X1), dried over sodiumsulfate and concentrated in vacuo. The residue was purified bypreparative TLC eluting with a 30% ethylacetate/n-hexane mixture to give2-chloro-1-methyl-7-(3-methyl-1H-pyrazol-1-yl)-1H-benzimidazole. Amixture 2-chloro-1-methyl-7-(3-methyl-1H-pyrazol-1-yl)-1H-benzimidazoleobtained above, 48 mg (0.223 mmol) of 4-bromo-2-methoxy-6-methylanilineand 0.15 mL of 1-methyl-2-pyrrolidinone was stirred at 120° C. for 3days. After cooling, the reaction mixture was neutralized by saturatedaqueous sodium hydrogen carbonate. The aqueous suspension was extractedwith ethyl acetate (X2). The combined organic layer was washed withwater (X1) and brine (X1), dried over sodium sulfate and concentrated invacuo. The residue was purified by preparative TLC eluting with a 75%ethylacetate/n-hexane mixture to give 5.7 mg (18%) of the titlecompound.

¹H NMR (CDCl₃) δ 2.17 (3H, s), 2.40 (3H, s), 3.23 (3H, s), 3.80 (3H, s),5.87 (1H, br s), 6.28 (1H, d, J=2.1 Hz), 6.92 (1H, d, J=2.4 Hz),7.00-7.13 (3H, m), 7.53 (1H, d, J=7.8 Hz), 7.63 (1H, d, J=2.1 Hz).

MS Calcd.: 425, 427. Found: 426, 428 (M+H).

Example 66N-(4-Bromo-2-methoxy-6-methylphenyl)-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazol-2-amine

7-Hydrazino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

To a suspension of 5.0 g (30.6 mmol) of7-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one in 16 mL ofconcentrated hydrochloric acid was added 8 mL of an aqueous solution of2.18 g (31.6 mmol) of sodium nitrite, the mixture was stirred at 0° C.for 30 minutes. Tin(II) chloride (18.0 g, 94.9 mmol) was dissolved in 10mL of concentrated hydrochloric acid, and the solution was added to thereaction mixture at 0° C. After one hour, the mixture was alkalified by12 N sodium hydroxide, followed by addition of ethyl acetate to thesuspension. After addition of 24.6 mL of di-tert-butyl dicarbonate (107mmol), the mixture was stirred at room temperature for 15 hours. Theaqueous layer was separated and extracted with ethyl acetate (X1). Theorganic layer was washed with brine (X1), dried over sodium sulfate andconcentrated in vacuo. The residual solids were washed with hexane togive 8.53 g of the Boc derivative of the title compound as yellowcrystals. A suspension of 8.53 g (17.8 mmol) of the Boc derivative ofthe title compound in 100 mL of 4 N hydrogen chloride in methanol wasstirred at room temperature for 12 hours. The resulting crystals werecollected by filtration and washed with methanol to give 3.17 g (52%) ofthe title compound.

¹H NMR (DMSO-d₆) δ 3.52 (3H, s), 6.79-6.82 (2H, m), 6.98 (1H, t, J=8.0Hz), 8.02 (1H, s), 10.03 (2H, s), 11.00 (1H, s).

7-(2,4-Diethyl-1H-pyrazol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

To a suspension of 211 mg (0.986 mmol) of7-hydrazino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one in 2 mL of aceticacid was added 0.13 mL (0.986 mmol) of 3,5-heptanedione, the mixture wasstirred at 100° C. for 2 hours. After cooling, the reaction mixture wasneutralized by saturated aqueous sodium hydrogen carbonate and extractedwith ethyl acetate (X2). The combined organic layer was washed withbrine (X1), dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluting with a50-80% ethylacetate/n-hexane gradient mixture to give 221 mg (83%) ofthe title compound.

¹H NMR (CDCl₃) δ 1.16 (3H, t, J=7.5 Hz), 1.29 (3H, t, J=7.8 Hz),2.35-2.53 (2H, br), 2.69 (2H, q, J=7.8 Hz), 2.85 (3H, s), 6.06 (1H, s),7.01 (1H, dd, J=7.8, 1.5 Hz), 7.08 (1H, t, J=7.8 Hz), 7.14 (1H, dd,J=7.8, 1.5 Hz), 9.49 (1H, br s).

2-Chloro-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazole

A mixture of 220 mg (0.814 mmol) of7-(2,4-diethyl-1H-pyrazol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-onein 2 mL of phosphorus oxychloride was stirred at 85° C. for 4 hours.After cooling, phosphorus oxychloride was evaporated in vacuo. Theresidue was diluted with ice-cold water and neutralized by aqueoussodium hydroxide. The aqueous suspension was extracted with ethylacetate (X2). The combined organic layer was washed with water (X1) andbrine (X1), dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluting with a25-50% ethylacetate/n-hexane gradient mixture to give 181 mg (77%) ofthe title compound.

¹H NMR (CDCl₃) δ 1.15 (3H, t, J=7.5 Hz), 1.30 (3H, t, J=7.5 Hz), 2.44(2H, q, J=7.5 Hz), 2.70 (2H, q, J=7.5 Hz), 3.20 (3H, s), 6.10 (1H, s),7.21 (1H, dd, J=7.8, 1.2 Hz), 7.30 (1H, t, J=7.8 Hz), 7.76 (1H, dd,J=7.8, 1.2 Hz).

MS Calcd.: 288, 290. Found: 289, 291 (M+H).

N-(4-Bromo-2-methoxy-6-methylphenyl)-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazol-2-amine

A mixture of 83 mg (0.287 mmol) of2-chloro-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazole, 186mg (0.862 mmol) of 4-bromo-2-methoxy-6-methylaniline and 0.15 mL of1-methyl-2-pyrrolidinone was stirred at 110° C. for 20 hours. Aftercooling, the reaction mixture was neutralized with saturated aqueoussodium hydrogen carbonate, followed by addition of ethyl acetate. Theresulting crystals were collected by filtration and washed with waterand ethyl acetate to give 112 mg (83%) of the title compound.

¹H NMR (CDCl₃) δ 1.18 (3H, t, J=7.4 Hz), 1.31 (3H, t, J=7.6 Hz), 2.17(3H, s), 2.49 (2H, q, J=7.4 Hz), 2.72 (2H, q, J=7.6 Hz), 3.07 (3H, s),3.81 (3H, s), 5.81 (1H, br s), 6.09 (1H, s), 6.93-7.16 (4H, m), 7.54(1H, d, J=8.8 Hz).

MS Calcd.: 467, 469. Found: 468, 470 (M+H).

Compounds described below were prepared in a similar method.

TABLE 6 Example Structure Name Physical Data 67

N-(4-bromo-2- methoxy-6- methylphenyl)-7- (3,5-dimethyl-1H-pyrazol-1-yl)- 1-methyl-1H- benzimidazol-2- amine ¹H NMR (CDCl₃) δ 2.16(3H, s), 2.18 (3H, s), 2.32 (3H, s), 3.10 (3H, s), 3.80 (3H, s), 6.04(1H, s), 6.29 (1H, br s), 6.93-6.97 (2H, m), 7.03 (1H, s), 7.10 (1H, t,J = 7.5 Hz), 7.50 (1H, d, J = 7.5 Hz). MS Calcd.: 439, 441; Found: 440,442 (M + H). 68

N-(4-bromo-2- methoxy-6- methylphenyl)- 7-(5-tert- butyl-3-methyl-1H-pyrazol-1- yl)-1-methyl-1H- benzimidazol-2- amine ¹H NMR (CDCl₃) δ1.18 (9H, s), 2.14 (3H, s), 2.31 (3H, s), 3.02 (3H, s), 3.80 (3H, s),5.79 (1H, s), 6.06 (1H, s), 6.91 (1H, d, J = 2.1 Hz), 7.03 (1H, d, J =2.1 Hz), 7.10 (2H, t, J = 4.5 Hz), 7.54 (1H, d, J = 4.5 Hz). MS Calcd.:481, 483; Found: 482, 484 (M + H).

Example 69N-(4-Bromo-2-methoxy-6-methylphenyl)-7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-benzimidazol-2-amine

7-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

To a suspension of 257 mg (1.57 mmol) of7-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one in 2 mL of aceticacid was added 0.18 mL (1.57 mmol) of 2,5-hexanedione, the mixture wasstirred at 90° C. for 1 hour. After cooling, the reaction mixture wasneutralized by saturated aqueous sodium hydrogen carbonate and extractedwith ethyl acetate (X2). The combined organic layer was washed withbrine (X1), dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluting with a25-50% ethylacetate/n-hexane gradient mixture to give 258 mg (68%) ofthe title compound.

¹H NMR (CDCl₃) δ 1.97 (6H, s), 2.79 (3H, s), 5.92 (2H, s), 6.93 (1H, dd,J=7.5, 1.5 Hz), 7.08-7.16 (2H, m), 9.45 (1H, s).

2-Chloro-7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-benzimidazole

A mixture of 239 mg (0.991 mmol) of7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-onein 2 mL of phosphorus oxychloride was stirred at 85° C. for 4 hours.After cooling, phosphorus oxychloride was evaporated in vacuo. Theresidue was diluted with ice and neutralized by aqueous sodiumhydroxide. The aqueous suspension was extracted with ethyl acetate (X2).The combined organic layer was washed with water (X1) and brine (X1),dried over sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with a 10-20%ethylacetate/n-hexane gradient mixture to give 185 mg (72%) of the titlecompound.

¹H NMR (CDCl₃) δ 1.94 (6H, s), 3.09 (3H, s), 5.95 (2H, s), 7.15 (1H, dd,J=7.8, 1.0 Hz), 7.32 (1H, t, J=7.8 Hz), 7.75 (1H, dd, J=7.8, 1.0 Hz).

MS Calcd.: 259. Found: 260 (M+H).

N-(4-Bromo-2-methoxy-6-methylphenyl)-7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-benzimidazol-2-amine

A mixture of 90 mg (0.347 mmol) of2-chloro-7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-benzimidazole and225 mg (1.04 mmol) of 4-bromo-2-methoxy-6-methylaniline was stirred at110° C. for 15 hours. After cooling, the reaction mixture wasneutralized by saturated aqueous sodium hydrogen carbonate and extractedwith ethyl acetate (X2). The combined organic layer was washed withbrine (X1), dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluting with a60-90% ethylacetate/n-hexane gradient mixture. The desired fractionswere collected and evaporated in vacuo, the residual solids were washedwith diethyl ether to give 53.4 mg (35%) of the title compound.

¹H NMR (CDCl₃) δ 1.99 (6H, s), 2.19 (3H, s), 2.96 (3H, s), 3.81 (3H, s),5.94 (2H, s), 6.92-6.96 (2H, m), 7.05 (1H, d, J=1.8 Hz), 7.15 (1H, t,J=7.5 Hz), 7.54 (1H, d, J=7.5 Hz).

MS Calcd.: 438, 440. Found: 439, 441 (M+H).

Example 70-71

Example 70 and 71 in Table 7 were prepared in the similar methoddescribed in Example 15.

TABLE 7 Example Structure Name Physical Data 70

N-(4-chloro-2- methoxy-6- methylphenyl)- 7-(3,5- dimethylisoxazol-4-yl)-1- methyl-1H- benzimidazol- 2-amine ¹H NMR (CDCl₃) δ: 2.17 (3H,s), 2.19 (3H, s), 2.33 (3H, s), 3.37 (3H, s), 3.82 (3H, s), 5.90 (1H, brs), 6.80-7.60 (5H, m). MS Calcd.: 396; Found: 397 (M + H). 71

N-(4-chloro-2- methoxy-6- methylphenyl)- 7-(2,6- dimethoxyphenyl)-1-methyl-1H- benzimidazol- 2-amine Trifluoroacetic acid salt ¹H NMR(CDCl₃) δ: 2.17 (3H, s), 3.07 (3H, s), 3.80 (3H, s), 3.82-4.12 (6H, m),6.78 (1H, d, J = 2.4 Hz), 6.89 (1H, d, J = 2.4 Hz), 6.89 (1H, d, J = 7.8Hz), 7.13 (1H, t, J = 7.8 Hz), 7.22-7.40 (3H, m), 7.51 (1H, d, J = 7.8Hz). MS Calcd.: 437; Found: 438 (M + H). mp 288-289° C.

Example 72N-(4-Bromo-2-methoxy-6-methylphenyl)-1-methyl-7-(3-methyl-5-phenyl-1H-pyrazol-1-yl)-1H-benzimidazol-2-amine

This compound was prepared in a similar manner described in Example 66.

¹H NMR (CDCl₃) δ: 2.13 (3H, s), 2.42 (3H, s), 3.19 (3H, s), 3.79 (3H,s), 5.81 (1H, br s), 6.45 (1H, s), 6.91-6.96 (2H, m), 7.03-7.08 (2H, m),7.23 (5H, s), 7.51 (1H, d, J=8.4 Hz). MS Calcd.: 501, 503. Found:502±504 (M+H).

Example 734-[1-(2-Hydroxyethyl)-2-(mesitylamino)-1H-benzimidazol-7-yl]heptan-4-ol

This compound was prepared in a similar manner described in Example 12.

mp 267-270° C.

¹H NMR (CD₃OD) δ: 1.24 (6H, t, J=7.5 Hz), 1.60-1.74 (4H, m), 2.16-2.40(4H, m), 2.52 (6H, s), 2.63 (3H, s), 4.47 (2H, t, J=4.8 Hz), 5.19 (2H,t, J=4.8 Hz), 7.22 (1H, dd, J=7.8, 1.2 Hz), 7.28 (2H, s), 7.32 (1H, t,J=7.8 Hz), 7.47 (1H, dd, J=7.8, 1.2 Hz). MS Calcd.: 409. Found: 410(M+H).

Example 742-[2-(Mesitylamino)-7-(1-propylbutyl)-1H-benzimidazol-1-yl]ethanol

This compound was prepared in a similar manner described previously inExample 14.

¹H NMR (CDCl₃) δ: 0.92 (6H, t, J=7.5 Hz), 1.20-1.40 (4H, m), 1.77-1.88(2H, m), 1.98-2.09 (2H, m), 2.53 (6H, s), 2.63 (3H, s), 2.87 (1H, m),4.21 (2H, t, J=4.8 Hz), 4.45 (2H, t, J=4.8 Hz), 7.22 (1H, dd, J=7.8, 1.2Hz), 7.27 (2H, s), 7.32 (1H, t, J=7.8 Hz), 7.46 (1H, dd, J=7.8, 1.2 Hz).

MS Calcd.: 393. Found: 394 (M+H).

Example 752-[2-[(4-Chloro-2-methoxy-6-methylphenyl)amino]-7-(1-hydroxy-1-propylbutyl)-1H-benzimidazol-1-yl]ethylacetate

A solution of4-[2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazol-7-yl]heptan-4-ol(100 mg, 0.22 mmol) in pyridine (5 mL) was treated with acetic anhydride(1 mL) and stirred at room temperature overnight. The reaction mixturewas concentrated to dryness, diluted with aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organics were driedover magnesium sulfate, filtered, and concentrated in vacuo. The residuewas chromatographed on a silica gel to give 97 mg (0.20 mmol, 89%) ofthe title compound.

¹H NMR (CDCl₃) δ: 0.92 (6H, t, J=7.5 Hz), 1.23-1.41 (4H, m), 1.81-1.91(2H, m), 1.98-2.09 (2H, m), 2.12 (3H, s), 2.15 (3H, s), 3.80 (3H, s),4.56 (2H, t, J=4.8 Hz), 4.85 (2H, t, J=4.8 Hz), 6.80 (1H, d, J=2.1 Hz),6.83 (1H, d, J=8.1 Hz), 6.88 (1H, d, J=2.1 Hz), 7.03 (1H, t, J=8.1 Hz),7.41 (1H, d, J=8.1 Hz). MS Calcd.: 487. Found: 488 (M+H).

Example 762-{2-[(4-Chloro-2-methoxy-6-methylphenyl)amino]-7-[(1E)-1-propylbut-1-en-1-yl]-1H-benzimidazol-1-yl}ethylacetate and2-{2-[(4-Chloro-2-methoxy-6-methylphenyl)amino]-7-[(1Z)-1-propylbut-1-en-1-yl]-1H-benzimidazol-1-yl}ethylacetate

A solution of2-[2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-hydroxy-1-propylbutyl)-1H-benzimidazol-1-yl]ethylacetate (50 mg, 0.10 mmol) and triethylsilane (1 mL) in diethyl ether(10 mL) was stirred at room temperature for 14 h. The reaction mixturewas diluted with aqueous sodium hydrogen carbonate, and extracted withethyl acetate. The organics were dried over magnesium sulfate, filtered,and concentrated in vacuo. The residue was chromatographed on a silicagel to give 11 mg (0.023 mmol, 23%) of the title compounds.

¹H NMR (CDCl₃) δ: 0.92 (6H, t, J=7.5 Hz), 1.28-1.49 (4H, m), 1.78-1.91(2H, m), 2.08 (3H, s), 2.17 (3H, s), 3.79 (3H, s), 4.20-4.41 (4H, m),5.57 (0.8H, t, J=7.2 Hz), 5.65 (0.2H, t, J=7.2 Hz), 6.75 (1H, d, J=7.2Hz), 6.80 (1H, d, J=2.1 Hz), 6.89 (1H, d, J=2.1 Hz), 7.04 (1H, t, J=7.2Hz), 7.41 (1H, d, J=7.2 Hz). MS Calcd.: 469. Found: 470 (M+H).

Example 77N-(4-Bromo-2-methoxy-6-methylphenyl)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

7-(1-Ethyl-1-hydroxypropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

A solution of ethylmagnesium bromide (3M solution in diethyl ether; 32mL, 96 mmol) was added dropwise to a suspension of methyl3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (5.00 g, 24.2mmol) in tetrahydrofuran (50 mL) at 0° C. The mixture was stirred at 40°C. overnight. The reaction was quenched with water and 1N HCl, extractedwith ethyl acetate, washed with brine. The organic layer was dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue wascrystallized from ethanol/diethylether to afford the title compound ascolorless crystals (3.39 g, 70%). mp 199-201° C.

¹H NMR (CDCl₃) δ 0.90 (t, J=7.5 Hz, 6H), 1.90-2.20 (m, 5H), 3.84 (s,3H), 6.90-7.05 (m, 3H), 9.10-9.30 (m, 1H).

MS Calcd.: 234. Found: 235 (M+H).

7-(1-Ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

A mixture of7-(1-ethyl-1-hydroxypropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one(6.00 g, 25.6 mmol) and 6N HCl (20 mL) in ethanol (100 mL) was stirredat 50° C. for 3 h. The mixture was concentrated in vacuo, and theresulting residue was dissolved in ethyl acetate, washed with aqueouspotassium carbonate. The organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo to give pale yellow oil, which wasused in the next reaction without further purification. MS Calcd.: 216.Found: 217 (M+H). The crude material was dissolved in ethanol (150 mL).This solution was treated with 10% palladium on carbon (50% wet; 1.00g), purged with hydrogen, and stirred under 5 atoms hydrogen for 7 h.The catalyst was removed by filtration and the filtrate was concentratedin vacuo. The residue was crystallized from ethanol/diethylether toafford the title compound as colorless crystals (3.02 g, 54%). mp130-132° C.

¹H NMR (CDCl₃) δ 0.82 (t, J=6.6 Hz, 6H), 1.60-1.85 (m, 4H), 3.15-3.25(m, 1H), 3.65 (s, 3H), 6.85-6.98 (m, 2H), 7.00-7.10 (m, 1H), 10.2-10.5(m, 1H).

MS Calcd.: 218. Found: 219 (M+H).

4-Chloro-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

2,2′-Azobisisobutyronitrile (AIBN) (94 mg, 0.57 mmol) was added to amixture of 7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one(2.90 g, 13.3 mmol) and N-chlorosuccinimide (1.95 g, 14.6 mmol) incarbon tetrachloride (250 mL). The mixture was stirred at 70° C. for 2days. The reaction was concentrated in vacuo, extracted with ethylacetate and washed with brine. The organic layer was dried overmagnesium sulfate, filtered, and concentrated in vacuo to give residue.The residue was crystallized from ethanol/iso-propanol to afford thetitle compound as colorless crystals (2.28 g, 68%). mp 165-166° C.

¹H NMR (CDCl₃) δ 0.81 (t, J=7.2 Hz, 6H), 1.60-1.85 (m, 4H), 3.10-3.20(m, 1H), 3.64 (s, 3H), 6.87 (d, J=8.7 Hz, 1H), 7.03 (d, J=8.7 Hz, 1H),8.55 (s, 1H). MS Calcd.: 251. Found: 252 (M+H).

2,4-Dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

A mixture of4-chloro-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one(1.17 g, 4.63 mmol) in phosphorous oxychloride (28 g) was stirred at 90°C. for 3 h. The reaction was allowed to cool to room temperature andconcentrated in vacuo. The residue was dissolved in ethyl acetate,washed with aqueous sodium bicarbonate and brine. The organic layer wasdried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was subjected to chromatography on silica gel (n-hexane/ethylacetate=10:1-1:1) and crystallized from ethyl acetate-hexane to affordthe title compound as colorless crystals (1.03 g, 82%). mp 94-95° C.

¹H NMR (CDCl₃) δ 0.82 (t, J=7.5 Hz, 6H), 1.60-1.90 (m, 4H), 3.20-3.30(m, 1H), 4.01 (s, 3H), 7.05 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H).MS Calcd.: 270. Found: 271 (M+H).

N-(4-Bromo-2-methoxy-6-methylphenyl)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

A mixture of 2,4-dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole(140 mg, 0.52 mmol), 4-bromo-2-methoxy-6-methylaniline (335 mg, 1.55mmol) and 1-methyl-2-pyrrolidone (5 drops) was stirred at 130° C. for 2days under nitrogen atmosphere. The mixture was dissolved in ethylacetate/water, extracted with ethyl acetate and washed with brine. Theorganic layer was dried over magnesium sulfate, and concentrated to givea brown oil. The oil was subjected to chromatography on a silica gel(n-hexane/ethyl acetate=10:1-1:1) and crystallized from iso-propanol toafford the title compound as colorless crystals (115 mg, 49%). mp.218-220° C.

¹H NMR (CDCl₃) δ 0.83 (t, J=7.2 Hz, 6H), 1.60-1.85 (m, 4H), 2.15 (s,3H), 3.10-3.25 (m, 1H), 3.76 (s, 3H), 3.79 (s, 3H), 6.08 (s, 1H), 6.86(d, J=8.4 Hz, 1H), 6.91 (s, 1H), 7.03 (s, 1H), 7.10-7.20 (m, 1H). MSCalcd.: 449. Found: 450 (M+H).

Examples 78-96 were prepared in the similar method described in Example77.

Example 784-Chloro-N-(4-chloro-2-methoxy-6-methylphenyl)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp 219-221° C.

¹H NMR (CDCl₃) δ 0.83 (t, J=7.2 Hz, 6H), 1.60-1.85 (m, 4H), 2.16 (s,3H), 3.10-3.20 (m, 1H), 3.75 (s, 3H), 3.79 (s, 3H), 6.07 (s, 1H), 6.77(d, J=2.1 Hz, 1H), 6.80-6.90 (m, 2H), 7.05-7.20 (m, 1H).

MS Calcd.: 405. Found: 406 (M+H).

Example 794-Chloro-N-[2,6-dichloro-4-(trifluoromethoxy)phenyl]-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp 147-149° C.

¹H NMR (CDCl₃) δ 0.85 (t, J=7.2 Hz, 6H), 1.60-1.85 (m, 4H), 3.10-3.20(m, 1H), 3.87 (s, 3H), 6.75-6.90 (m, 1H), 6.98 (d, J=8.4 Hz, 1H),7.20-7.45 (m, 2H), 8.30-8.40 (m, 1H).

MS Calcd.: 479. Found: 480 (M+H).

Example 804-Chloro-N-(2,4-dichlorophenyl)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp 130-132° C.

¹H NMR (CDCl₃) δ 0.84 (t, J=7.5 Hz, 6H), 1.60-1.85 (m, 4H), 3.15-3.25(m, 1H), 3.84 (s, 3H), 6.72 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 7.21 (d,J=8.4 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 8.09 (d,J=8.4 Hz, 1H).

MS Calcd.: 395. Found: 396 (M+H).

Example 814-Chloro-N-[4-chloro-2-(trifluoromethoxy)phenyl]-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp 126-128° C.

¹H NMR (CDCl₃) δ 0.84 (t, J=7.5 Hz, 6H), 1.60-1.85 (m, 4H), 3.15-3.30(m, 1H), 3.87 (s, 3H), 6.81 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 7.20-7.40(m, 3H), 8.30-8.40 (m, 1H). MS Calcd.: 445. Found: 446 (M+H).

Example 82N-(4-Bromo-2,6-dimethylphenyl)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp 247-249° C.

¹H NMR (CDCl₃) δ 0.82 (t, J=7.5 Hz, 6H), 1.55-1.80 (m, 4H), 2.17 (s,6H), 3.00-3.20 (m, 1H), 3.40-3.65 (m, 3H), 5.90-6.00 (m, 1H), 6.70-6.90(m, 2H), 7.00-7.20 (m, 1H), 7.20-7.30 (m, 1H). MS Calcd.: 434. Found:435 (M+H).

Example 834-Chloro-N-(4-chloro-2,6-dimethylphenyl)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp 247-249° C.

¹H NMR (CDCl₃) δ 0.82 (t, J=7.5 Hz, 6H), 1.55-1.80 (m, 4H), 2.18 (s,6H), 3.00-3.20 (m, 1H), 3.40-3.65 (m, 3H), 5.90-6.00 (m, 1H), 6.70-6.90(m, 2H), 7.05-7.20 (m, 2H).

MS Calcd.: 389. Found: 390 (M+H).

Example 84N-(2-Bromo-4-chlorophenyl)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp 136-138° C.

¹H NMR (CDCl₃) δ 0.84 (t, J=7.5 Hz, 6H), 1.60-1.85 (m, 4H), 3.15-3.25(m, 1H), 3.84 (s, 3H), 6.81 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 7.21 (d,J=8.4 Hz, 1H), 7.32 (dd, J=8.4, 2.4 Hz, 1H), 7.56 (d, J=2.4 Hz, 1H),8.06 (d, J=8.4 Hz, 1H). MS Calcd.: 440. Found: 441 (M+H).

Example 85N-(4-Bromo-2-chlorophenyl)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp 127-129° C.

¹H NMR (CDCl₃) δ 0.84 (t, J=7.5 Hz, 6H), 1.60-1.85 (m, 4H), 3.15-3.25(m, 1H), 3.85 (s, 3H), 6.80 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 7.22 (d,J=8.4 Hz, 1H), 7.42 (dd, J=8.8, 2.4 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H),8.03 (d, J=8.8 Hz, 1H). MS Calcd.: 440. Found: 441 (M+H).

Example 86N-(2-Bromo-4-methylphenyl)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp 174-176° C.

¹H NMR (CDCl₃) δ 0.84 (t, J=7.5 Hz, 6H), 1.60-1.85 (m, 4H), 2.30 (s,3H), 3.15-3.25 (m, 1H), 3.80 (s, 3H), 6.74 (s, 1H), 6.94 (d, J=8.4 Hz,1H), 7.10-7.15 (m, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.38 (d, J=1.2 Hz,1H)-7.77 (d, J=8.4 Hz, 1H). MS Calcd.: 420. Found: 421 (M+H).

Example 874-Chloro-N-[2-chloro-4-(trifluoromethoxy)phenyl]-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp 122-123° C.

¹H NMR (CDCl₃) δ 0.84 (t, J=7.5 Hz, 6H), 1.60-1.85 (m, 4H), 3.15-3.25(m, 1H), 3.87 (s, 3H), 6.81 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 7.21 (d,J=8.4 Hz, 2H), 7.31 (s, 1H), 8.21 (d, J=8.4 Hz, 1H). MS Calcd.: 445.Found: 446 (M+H).

Example 88N⁵-[4-Chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-yl]-N²,N²,4-trimethylpyridine-2,5-diamine

mp 224-226° C.

¹H NMR (CDCl₃) δ 0.82 (t, J=7.2 Hz, 6H), 1.60-1.85 (m, 4H), 2.26 (s,3H), 3.00-3.20 (m, 1H), 3.07 (s, 6H), 3.59 (s, 3H), 5.90 (s, 1H), 6.41(s, 1H), 6.87 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.91 (s, 1H).MS Calcd.: 385. Found: 386 (M+H).

Example 89N-(4-Bromo-2-methoxy-6-methylphenyl)-4-chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amine

mp 210-211° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.15-1.35 (m, 4H), 1.60-1.80(m, 4H), 2.15 (s, 3H), 3.25-3.40 (m, 1H), 3.75 (s, 3H), 3.79 (s, 3H),6.07 (s, 1H), 6.85-6.95 (m, 2H), 7.00-7.20 (m, 2H). MS Calcd.: 477.Found: 478 (M+H).

Example 904-Chloro-N-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amine

mp 204-206° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.2 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.75(m, 4H), 2.15 (s, 3H), 3.25-3.40 (m, 1H), 3.75 (s, 3H), 3.79 (s, 3H),6.08 (s, 1H), 6.77 (d, J=2.1 Hz, 1H), 6.80-6.90 (m, 2H), 7.10 (d, J=8.4Hz, 1H). MS Calcd.: 433. Found: 434 (M+H).

Example 914-Chloro-N-(2,4-dichlorophenyl)-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amine

mp 146-148° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.2 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.80(m, 4H), 3.30-3.45 (m, 1H), 3.84 (s, 3H), 6.79 (s, 1H), 6.97 (d, J=8.1Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.41 (d, J=2.4Hz, 1H), 8.09 (d, J=8.4 Hz, 1H). MS Calcd.: 423. Found: 424 (M+H).

Example 92N-(2-Bromo-4-chlorophenyl)-4-chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amine

mp 145-147° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.80(m, 4H), 3.30-3.45 (m, 1H), 3.84 (s, 3H), 6.80 (s, 1H), 7.00 (d, J=8.1Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.31 (dd, J=8.7, 2.4 Hz, 1H), 7.55 (d,J=2.4 Hz, 1H), 8.04 (d, J=8.7 Hz, 1H). MS Calcd.: 469. Found: 470 (M+H).

Example 93N-(4-Bromo-2-chlorophenyl)-4-chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amine

mp 145-147° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.80(m, 4H), 3.30-3.45 (m, 1H), 3.84 (s, 3H), 6.79 (s, 1H), 7.00 (d, J=8.1Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.41 (dd, J=9.0, 2.4 Hz, 1H), 7.54 (d,J=2.4 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H). MS Calcd.: 469. Found: 470 (M+H).

Example 944-Chloro-N-[4-chloro-2-(trifluoromethoxy)phenyl]-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amine

mp 130-132° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.80(m, 4H), 3.30-3.40 (m, 1H), 3.81 (s, 3H), 6.56 (s, 1H), 6.97 (d, J=8.1Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.25-7.30 (m, 2H), 8.00-8.20 (m, 1H).MS Calcd.: 473. Found: 474 (M+H).

Example 954-Chloro-N-[2-chloro-4-(trifluoromethyl)phenyl]-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp 128-129° C.

¹H NMR (CDCl₃) δ 0.84 (6H, t, J=7.4 Hz) 1.65-1.88 (4H, m) 3.14-3.27 (1H,m) 3.88 (3H, s) 6.94-7.04 (2H, m) 7.20-7.28 (1H, m) 7.55 (1H, dd, J=8.8,1.9 Hz) 7.66 (1H, d, J=1.9 Hz) 8.20 (1H, d, J=9.9 Hz)

MS Calcd.: 429. Found: 430 (M+H).

Example 964-Bromo-N-(4-chloro-2-methoxy-6-methylphenyl)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp 198-199° C.

¹H NMR (CDCl₃) δ 0.83 (t, J=7.2 Hz, 6H), 1.60-1.80 (m, 4H), 2.17 (s,3H), 3.15 (m, 1H), 3.72 (s, 3H), 3.78 (s, 3H), 6.11 (bs, 1H), 6.77 (s,1H), 6.81 (d, J=8.4 Hz, 1H), 6.87 (s, 1H), 7.20-7.30 (m, 1H).

MS Calcd.: 449. Found: 450 (M+H).

Example 974-Chloro-2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

A solution of 2,4-dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole(5.5 g, 20.2 mmol), 2,4-dichloro-6-methylphenol (10 g, 56.5 mmol) andpotassium carbonate (8.4 g, 60.8 mmol) in N,N-dimethylformamide (55 mL)was heated at 100° C. for 9 h. To the mixture was added2,4-dichloro-6-methylphenol (5 g, 28.3 mmol) and potassium carbonate(4.2 g, 30.4 mmol) and heated at 100° C. for 16 h. Additional2,4-dichloro-6-methylphenol (5 g, 28.3 mmol) and potassium carbonate(4.2 g, 30.4 mmol) were added and heated at 100° C. for 9 h. Aftercooling, the mixture was diluted with water and extracted with ethylacetate. The extract was washed with brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on NH silica gel eluting with a 12.5% ethylacetate/n-hexane. The resulting solids were recrystallized from a 10%ethyl acetate/n-hexane to give 5.3 g (64%) of the title compound as acolorless crystal.

mp 155-157° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.2 Hz, 6H), 1.64-1.86 (m, 4H), 2.31 (s,3H), 3.17-3.28 (m, 1H), 3.99 (s, 3H), 6.93 (d, J=8.4 Hz, 1H), 7.14 (d,J=8.4 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H).

MS Calcd.: 410. Found: 411 (M+H).

Examples 98-99 were prepared in the similar method described in Example97.

Examples 984-Chloro-2-(2,4-dichlorophenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

mp 87-89° C.

¹H NMR (CDCl₃) δ 0.84 (6H, t, J=7.3 Hz) 1.63-1.88 (4H, m) 3.16-3.28 (1H,m) 3.97 (3H, s) 6.96 (1H, d, J=8.2 Hz) 7.18 (1H, d, J=8.2 Hz) 7.32 (1H,dd, J=8.8, 2.5 Hz) 7.47 (1H, d, J=2.5 Hz) 7.74 (1H, d, J=8.8 Hz).

MS Calcd.: 396. Found: 397 (M+H).

Examples 994-Chloro-7-(1-ethylpropyl)-2-(mesityloxy)-1-methyl-1H-benzimidazole

mp 137-139° C.

¹H NMR (CDCl₃) δ 0.87 (6H, t, J=7.4 Hz) 1.65-1.87 (4H, m) 2.17 (6H, s)2.30 (3H, s) 3.17-3.29 (1H, m) 3.97 (3H, s) 6.87-6.95 (3H, m) 7.12 (1H,d, J=8.2 Hz).

MS Calcd.: 370. Found: 371 (M+H).

Examples 100N-(4-Chloro-2-methoxy-6-methylphenyl)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazol-2-amine

7-(1-Ethylpropyl)-4-methoxy-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

A solution of4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one(250 mg, 0.841 mmol), anhydrous cuprus iodide (192 mg, 1.01 mmol) and28% sodium methoxide in methanol (5.2 mL) in N,N-dimethylformamide (5mL) was heated at 100° C. for 1 h. After cooling, the mixture wasdiluted with water and extracted with ethyl acetate. The organics weredried over magnesium sulfate, filtered and concentrated in vacuo to givethe title compound (190 mg, 0.765 mmol, 91%).

¹H NMR (CDCl₃) δ 0.81 (6H, t, J=7.5 Hz), 1.65-1.80 (4H, m), 3.05-3.15(1H, m), 3.63 (3H, s), 3.90 (3H, s), 6.63 (1H, d, J=8.4 Hz), 6.85 (1H,d, J=8.4 Hz), 8.39 (1H, br).

MS Calcd.: 248. Found: 249 (M+H).

2-Chloro-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole

A mixture of7-(1-ethylpropyl)-4-methoxy-1-methyl-1,3-dihydro-2H-benzimidazol-2-one(190 mg, 0.765 mmol) in phosphorous oxychloride (2.14 mL) was stirred at110° C. for 6 h. The reaction was allowed to cool to room temperatureand concentrated in vacuo. The residue was dissolved in ethyl acetateand washed with aqueous sodium bicarbonate and brine. The organic layerwas dried over magnesium sulfate, filtered, and concentrated in vacuo.The residue was purified by column chromatography on silica gel(n-hexane/ethyl acetate 10:1-1:1) and crystallized from ethylacetate/n-hexane to afford the title compound as colorless crystals (123mg, 60%).

MS Calcd.: 266. Found: 267 (M+H).

N-(4-Chloro-2-methoxy-6-methylphenyl)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazol-2-amine

A mixture of2-chloro-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole (120 mg,0.450 mmol), 4-chloro-2-methoxy-6-methylaniline (231 mg, 1.35 mmol) and1-methyl-2-pyrrolidone (0.5 mL) was stirred at 130° C. for 2 days undernitrogen atmosphere. The mixture was diluted with water, extracted withethyl acetate and washed with brine. The organic layer was dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedby column chromatography on silica gel (n-hexane/ethyl acetate=10:1-1:1)and crystallized from iso-propanol to afford the title compound ascolorless crystals (100 mg, 55%).

mp 188-189° C.

¹H NMR (CDCl₃) δ 0.85 (t, J=7.2 Hz, 6H), 1.60-1.80 (m, 4H), 2.08 (s,3H), 3.10-3.20 (m, 1H), 3.79 (s, 3H), 3.82 (s, 3H), 3.90 (s, 3H), 5.89(m, 1H), 6.61 (d, J=8.7 Hz, 1H), 6.75 (d, J=1.8 Hz, 1H), 6.83 (d, J=1.8Hz, 1H), 6.86 (d, J=8.7 Hz, 1H). MS Calcd.: 401. Found: 402 (M+H).

Examples 101N-(4-Chloro-2-methoxy-6-methylphenyl)-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazol-2-amine

7-(1-Ethylpropyl)-1,4-dimethyl-1,3-dihydro-2H-benzimidazol-2-one

A solution of4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one(250 mg, 0.84 mmol), tetrakis(triphenylphosphine)palladium (194 mg,0.168 mmol), tetramethyltin (1.16 mL, 8.4 mmol) in hexamethylphosphorictriamide (5 mL) was refluxed for 18 h. After cooling, the mixture wasdiluted with water and extracted with dichloromethane. The organics weredried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography on a silica gel(n-hexane/ethyl acetate=90:10-50:50) to give the title compound (111 mg,0.48 mmol, 57%).

¹H NMR (CDCl₃) δ 0.82 (6H, t, J=7.5 Hz), 1.55-1.80 (4H, m), 2.38 (3H,s), 3.10-3.20 (1H, m), 3.65 (3H, s), 6.84 (1H, d, J=8.4 Hz), 6.87 (1H,d, J=8.4 Hz), 10.15 (1H, br).

MS Calcd.: 232. Found: 233 (M+H).

2-Chloro-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazole

A mixture of7-(1-ethylpropyl)-1,4-dimethyl-1,3-dihydro-2H-benzimidazol-2-one (105mg, 0.452 mmol) in phosphorous oxychloride (1.23 mL) was stirred at 110°C. for 3 h. The reaction was allowed to cool to room temperature andconcentrated in vacuo. The residue was dissolved in ethyl acetate,washed with aqueous sodium bicarbonate and brine. The organic layer wasdried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(n-hexane/ethyl acetate=10:1-1:1) and crystallized from ethylacetate/n-hexane to afford the title compound as colorless crystals (100mg, 88%).

MS Calcd.: 250. Found: 251 (M+H).

N-(4-Chloro-2-methoxy-6-methylphenyl)-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazol-2-amine

A mixture of 2-chloro-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazole(100 mg, 0.399 mmol), 4-chloro-2-methoxy-6-methylaniline (205 mg, 1.20mmol) and 1-methyl-2-pyrrolidone (0.2 mL) was stirred at 120° C. for 2days under nitrogen atmosphere. The mixture was diluted with water andextracted with ethyl acetate, washed with brine. The organic layer wasdried over magnesium sulfate, and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (n-hexane:ethylacetate=10:1-1:1) and crystallized from iso-propanol to afford the titlecompound as colorless crystals (53 mg, 34%).

mp 201-202° C.

¹H NMR (CDCl₃) δ 0.85 (t, J=7.2 Hz, 6H), 1.60-1.80 (m, 4H), 2.11 (s,3H), 2.45 (s, 3H), 3.10-3.20 (m, 1H), 3.78 (s, 3H), 3.81 (s, 3H), 6.00(m, 1H), 6.78 (d, J=2.1 Hz, 1H), 6.80-6.95 (m, 3H). MS Calcd.: 385.Found: 386 (M+H).

Example 102Isopropyl[4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate

Methyl 2,3-diaminobenzoate

To a suspension of methyl 2-amino-3-nitrobenzoate (15 g, 76.5 mmol) inmethanol (800 mL) was added 10% palladium on carbon (50% wet; 6.5 g),and the mixture was stirred at room temperature for 20 hours underhydrogen atmosphere. The catalyst was removed by filtration, and thefiltrate was concentrated in vacuo. The residual solid was crystallizedfrom diisopropyl ether-hexane to give 11.57 g (69.6 mmol, 91.0%) of thetitle compound as a dark yellow needle.

¹H NMR (CDCl₃) δ: 3.33 (2H, br s), 3.07 (3H, s), 5.56 (2H, br s), 6.60(1H, dd, J=8.1, 7.5 Hz), 6.85 (1H, dd, J=7.5, 1.5 Hz), 7.47 (1H, dd,J=8.1, 1.5 Hz).

MS Calcd.: 166. Found: 167 (M+H).

Methyl 2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate

To a solution of methyl 2,3-diaminobenzoate (10.5 g, 63.2 mmol) intetrahydrofuran (100 mL) was added N,N′carbonyldiimidazole (10.2 g, 63.2mmol), and the mixture was stirred at room temperature for 60 hours. Theresulting solid was collected by filtration and washed with ethylacetate to give 10.2 g (53.1 mmol, 84.0%) of the title compound as acolorless crystal.

¹H NMR (DMSO-d₆) δ: 3.87 (3H, s), 7.03 (1H, dd, J=8.1, 7.5 Hz), 6.85(1H, dd, J=7.5, 1.2 Hz), 7.48 (1H, dd, J=8.1, 1.2 Hz), 10.82 (2H, br s).

MS Calcd.: 192. Found: 193 (M+H).

4-(1-Ethyl-1-hydroxypropyl)-1,3-dihydro-2H-benzimidazol-2-one

To a suspension of methyl2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (513 mg, 2.67 mmol) intetrahydrofuran (5 mL) was added 3M solution of ethyl magnesium bromidein diethyl ether (3.6 ml, 10.7 mmol), and the mixture was stirred atroom temperature for 1 hour and refluxed for 20 hours. Addition of 3Msolution of ethyl magnesium bromide in diethyl ether (5.3 mL, 16.0 mmol)was followed by refluxing for 30 hours. The reaction mixture wasacidified with 6 N hydrochloric acid and extracted with ethyl acetate(X2). The combined organic layer was washed with brine (X1), dried oversodium sulfate and concentrated in vacuo. The resulting solid was washedwith diisopropyl ether to give 440 mg (2.00 mmol, 74.8%) of the titlecompound.

¹H NMR (CDCl₃) δ: 0.83 (6H, t, J=7.5 Hz), 1.76-1.98 (4H, m), 2.19 (1H,br s), 6.72 (1H, d, J=7.8 Hz), 6.92-7.02 (2H, m), 9.16 (1H, br s), 9.44(1H, br s).

MS Calcd.: 220. Found: 203 (M−H₂O+H).

4-[(1E)-1-Ethylprop-1-en-1-yl]-1,3-dihydro-2H-benzimidazol-2-one and4-[(1Z)-1-Ethylprop-1-en-1-yl]-1,3-dihydro-2H-benzimidazol-2-one

To a solution of4-(1-ethyl-1-hydroxypropyl)-1,3-dihydro-2H-benzimidazol-2-one (410 mg,1.86 mmol) in ethanol (6 mL) was added 6N hydrochloric acid (1.2 mL),and the mixture was stirred at 75° C. for 2 hours. After cooling, thereaction mixture was diluted with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate (X2). The combined organiclayer was washed with water (X1) and brine (X1), dried over sodiumsulfate, passed through silica gel and concentrated in vacuo to give 364mg (1.80 mmol, 96.8%) of the title compound as a pale yellow solid.

¹H NMR (CDCl₃) δ: 0.95 (3H, t, J=7.5 Hz), 1.49 (0.75H, d, J=6.9 Hz),1.84 (2.25H, d, J=6.9 Hz), 2.36 (0.5H, q, J=7.5 Hz), 2.50 (1.5H, q,J=7.5 Hz), 5.62-5.75 (1H, m), 6.82-7.08 (3H, m), 8.29 (0.25H, s), 8.42(0.75H, s), 9.30 (1H, s).

MS Calcd.: 202. Found: 203 (M+H).

4-(1-Ethylpropyl)-1,3-dihydro-2H-benzimidazol-2-one

To a suspension of a mixture of4-[(1E)-1-ethylprop-1-en-1-yl]-1,3-dihydro-2H-benzimidazol-2-one and4-[(1Z)-1-ethylprop-1-en-1-yl]-1,3-dihydro-2H-benzimidazol-2-one (329mg, 1.63 mmol) and ammonium formate (820 mg, 13.0 mmol) in ethanol (3mL) was added 10% palladium on carbon (50% wet; 120 mg), and the mixturewas stirred at room temperature for 15 hours. The catalyst was removedby filtration, and the filtrate was concentrated in vacuo. The residuewas diluted with water and extracted with ethyl acetate (X1). Theorganic layer was washed with brine (X1), dried over sodium sulfate andconcentrated in vacuo to give 354 mg (>99%) of the title compound as acolorless solid.

¹H NMR (CDCl₃) δ: 0.80 (6H, t, J=7.2 Hz), 1.57-1.82 (4H, m), 2.50-2.62(1H, m), 6.88 (1H, d, J=7.8 Hz), 6.92 (1H, d, J=7.8 Hz), 7.03 (1H, t,J=7.8 Hz), 9.44 (1H, s), 9.54 (1H, s).

MS Calcd.: 204. Found: 205 (M+H).

tert-Butyl4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate

To a suspension of 4-(1-ethylpropyl)-1,3-dihydro-2H-benzimidazol-2-one(7.25 g, 35.5 mmol) in 1,2-dichloroethane (5 mL) was addedN,N-dimethylaminopyridine (4.34 g, 35.5 mmol) and di-tert-butyldicarbonate (8.16 ml, 35.5 mmol) at 0° C., and the mixture was stirredat 0° C. for 30 minutes. The reaction mixture was diluted with water andextracted with dichloromethane (X2). The combined organic layer waswashed with brine (X2), dried over sodium sulfate and concentrated invacuo. The residue was purified by silica gel column chromatographyeluting with a 5-40% ethyl acetate/hexane gradient mixture to give 7.87g (25.9 mmol, 72.8%) of the title compound as a colorless solid.

¹H NMR (CDCl₃) δ: 0.79 (6H, t, J=7.4 Hz), 1.55-1.83 (4H, m), 1.6.8 (9H,s), 2.40-2.60 (1H, m), 6.97 (1H, d, J=8.0 Hz), 7.09 (1H, t, J=8.0 Hz),7.65 (1H, d, J=8.0 Hz), 8.93 (1H, s).

tert-Butyl4-(1-ethylpropyl)-3-(2-isopropoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate

To a suspension of tert-butyl4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (7.70g, 25.3 mmol) in N,N-dimethylformamide (50 mL) was added potassiumcarbonate (3.84 g, 27.8 mmol) and isopropyl bromoacetate (3.60 ml, 27.8mmol), and the mixture was stirred at room temperature for 5 hours. Thereaction mixture was diluted with water and extracted with ethyl acetate(X2). The combined organic layer was washed with aqueous sodium chloride(X2) and brine (X1), dried over sodium sulfate and concentrated invacuo. The residue was purified by silica gel column, chromatographyeluting with a 5-20% ethyl acetate/hexane gradient mixture to give 8.95g (22.1 mmol, 87.5%) of the title compound as a colorless oil.

¹H NMR (CDCl₃) δ: 0.82 (6H, t, J=7.5 Hz), 1.26 (6H, d, J=6.3 Hz),1.53-1.76 (4H, m), 1.67 (9H, s), 2.57-2.68 (1H, m), 4.80 (2H, s),5.02-5.14 (1H, m), 7.03 (1H, dd, J=8.1, 1.5 Hz), 7.11 (1H, t, J=8.1 Hz),7.79 (1H, dd, J=8.1, 1.5 Hz).

Isopropyl[7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate

To a solution of tert-butyl4-(1-ethylpropyl)-3-(2-isopropoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate(8.95 g, 22.1 mmol) in ethyl acetate (10 ml) was added a 4N solution ofhydrogen chloride in ethyl acetate (20 ml), and the mixture was stirredat room temperature for 1 hour. The reaction mixture was diluted withsaturated aqueous sodium hydrogen carbonate and extracted with ethylacetate (X2). The combined organic layer was washed with brine (X1),dried over sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with a 5-20% ethylacetate/hexane gradient mixture. The residual solid was washed withhexane to give 5.76 g (18.9 mmol, 85.6%) of the title compound as acolorless solid.

¹H NMR (CDCl₃) δ: 0.81 (6H, t, J=7.5 Hz), 1.26 (6H, d, J=6.3 Hz),1.55-1.79 (4H, m), 2.62-2.73 (1H, m), 4.82 (2H, s), 5.05-5.15 (1H, m),6.90-6.94 (2H, m), 7.04 (1H, d, J=7.8 Hz), 9.12 (1H, s).

MS Calcd.: 304. Found: 305 (M+H).

Isopropyl[4-chloro-7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate

To a solution ofisopropyl[7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate(5.29 g, 17.4 mmol) in carbon tetrachloride (350 mL) was addedN-chlorosuccinimide (2.55 g, 19.1 mmol) and 2,2′-azobisisobutyronitrile(86 mg, 0.522 mmol), and the mixture was stirred at 70° C. for 3 days.The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate and extracted with dichloromethane (X2). The combined organiclayer was washed with water (X1) and brine (X1), dried over sodiumsulfate and concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with a 10-50% ethyl acetate/hexanegradient mixture to give 3.83 g (11.3 mmol, 65.0%) of the title compoundas a colorless solid.

¹H NMR (CDCl₃) δ: 0.83 (6H, t, J=7.5 Hz), 1.27 (6H, d, J=6.3 Hz),1.57-1.78 (4H, m), 2.59-2.68 (1H, m), 4.80 (2H, s), 5.02-5.14 (1H, m),6.86 (1H, d, J=8.7 Hz), 7.04 (1H, d, J=8.7 Hz), 8.67 (1H, s).

MS Calcd.: 338. Found: 339 (M+H).

Isopropyl[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate

A mixture ofisopropyl[4-chloro-7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate(3.73 g, 11.0 mmol) and phosphorus oxychloride (20 mL) was stirred at100° C. for 48 hours. After cooling, phosphorus oxychloride wasevaporated in vacuo. The residue was neutralized with saturated aqueoussodium hydrogen carbonate and extracted with ethyl acetate (X2). Thecombined organic layer was washed with brine (X1), dried over sodiumsulfate and concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with a 5-15% ethyl acetate/hexanegradient mixture to give 3.82 g (10.7 mmol, 97.2%) of the title compoundas an oil.

¹H NMR (CDCl₃) δ: 0.81 (6H, t, J=7.5 Hz), 1.28 (6H, d, J=6.3 Hz),1.62-1.83 (4H, m), 2.72-2.82 (1H, m), 5.06-5.21 (1H, m), 5.08 (2H, s),7.05 (1H, d, J=8.0 Hz), 7.28 (1H, d, J=8.0 Hz)

MS Calcd.: 356, 358. Found: 357, 359 (M+H).

Isopropyl[4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate

A mixture ofisopropyl[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate(1.60 g, 4.48 mmol), (4-chloro-2-methoxy-6-methyl)aniline (3.18 g, 18.6mmol) and N-methyl-2-pyrrolidinone (1 mL) was stirred at 110° C. for 4.5days. After cooling, the reaction mixture was diluted with saturatedaqueous sodium hydrogen carbonate and extracted with ethyl acetate (X1).The organic layer was washed with brine (X1), dried over sodium sulfateand concentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with a 5-20% ethyl acetate/hexane gradientmixture. The residual solid was washed with ethyl acetate/diisopropylether and n-hexane to give 1.18 g (2.40 mmol, 53.5%) of the titlecompound as a colorless solid. The filtrate was purified by preparativeHPLC to give 204 mg (0.414 mmol, 9.2%) of the title compound as a solid.mp 205-207° C.

¹H NMR (CDCl₃) δ: 0.82 (6H, t, J=7.4 Hz), 1.30 (6H, d, J=6.3 Hz),1.58-1.81 (4H, m), 2.11 (3H, s), 2.80-2.92 (1H, m), 3.83 (3H, s), 4.89(2H, s), 5.09-5.20 (1H, m), 6.56 (1H, s), 6.78 (1H, s), 6.87 (1H, d,J=7.6 Hz), 6.87 (1H, s), 7.14 (1H, d, J=7.6 Hz).

MS Calcd.: 491, 493. Found: 492, 494 (M+H).

Example 1032-[4-Chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]ethanol

To a solution ofisopropyl[4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate(453 mg, 0.920 mmol) in tetrahydrofuran (5 mL) was added lithiumtetrahydroborate (60 mg, 2.76 mmol), and the mixture was refluxed for 2hours. After cooling, the reaction mixture was diluted with water andextracted with ethyl acetate (X2). The combined organic layer was washedwith brine (X1), dried over sodium sulfate and concentrated in vacuo.The residual solid was recrystallized with ethyl acetate-n-hexane togive 250 mg (0.573 mmol, 62.3%) of the title compound as a colorlesscrystal. The filtrate was concentrated in vacuo, and the residual solidwas recrystallized with ethyl acetate-hexane to give 91 mg (0.209 mmol,22.7%) of the title compound as a colorless crystal.

¹H NMR (CDCl₃) δ: 0.85 (6H, t, J=7.2 Hz), 1.65-1.83 (4H, m), 2.16 (3H,s), 2.45-2.60 (1H, br), 2.79-2.87 (1H, m), 3.76 (3H, s), 4.14 (2H, t,J=4.5 Hz), 4.43 (2H, t, J=4.5 Hz), 6.76 (1H, d, J=1.8 Hz), 6.83 (1H, d,J=7.8 Hz), 6.87 (1H, d, J=1.8 Hz), 6.99 (1H, d, J=7.8 Hz), 7.50-7.70(1H, br).

MS Calcd.: 435, 437. Found: 436, 438 (M+H).

Example 104[4-Chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]aceticacid

To a solution of2-[4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]ethanol(861 mg, 1.75 mmol) in methanol (5 mL) was added 8N aqueous sodiumhydroxide (1.5 mL), and the mixture was stirred at room temperature for15 hours. Water was added to the reaction mixture, followed byneutralization with 6N hydrochloric acid. The mixture was concentratedin vacuo, and the residue was dissolved in methanol. The precipitate wasremoved by filtration, and the filtrate was concentrated in vacuo togive 781 mg (1.73 mmol, 99.1%) of the title compound as an amorphous.

¹H NMR (CDCl₃) δ: 0.76 (6H, t, J=7.2 Hz), 1.52-1.73 (4H, m), 2.07 (3H,s), 3.06-3.15 (1H, m), 3.76 (3H, s), 4.77 (2H, s), 6.77 (1H, d, J=8.4Hz), 6.93-6.99 (3H, m), 8.64 (1H, s).

MS Calcd.: 449, 451. Found: 450, 452 (M+H).

Example 1051-{4-Chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl}-2,2-dimethylpropan-1-one

Methyl7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate

A solution of methyl3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (500 mg, 2.42mmol), N-chlorosuccinimide (355 mg, 2.66 mmol) and2,2′-azobis(isobutyronitrile) (20 mg, 0.12 mmol) in carbon tetrachloride(40 mL) was refluxed for 2 days. After cooling, the reaction mixture wasconcentrated in vacuo. The resultant was extracted with ethyl acetateand water. The organics was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was chromatographed on a silica gelto give 167 mg (0.07 mmol, 29%) of the title compound.

¹H NMR (CDCl₃) δ 3.57 (3H, s), 3.95 (3H, s), 7.07 (1H, d, J=8.4 Hz),7.50 (1H, d, J=8.4 Hz), 8.03 (1H, br).

MS Calcd.: 240. Found: 241 (M+H).

Methyl 2,4-dichloro-1-methyl-1H-benzimidazole-7-carboxylate

Methyl7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (150mg, 0.63 mmol) was dissolved in 3 mL of phosphorous oxychloride andheated at 110° C. overnight. The reaction mixture was allowed to cool toroom temperature, poured into a crushed ice, and stirred for 1 h. Theresultant was diluted in ethyl acetate, washed with aqueous sodiumbicarbonate, dried over magnesium sulfate, filtered and concentrated invacuo. The obtained (147 mg, 90%) was used in the next reaction withoutfurther purification.

MS Calcd.: 257. Found: 258 (M+H).

Methyl4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazole-7-carboxylate

A mixture of methyl 2,4-dichloro-1-methyl-1H-benzimidazole-7-carboxylate(100 mg, 0.39 mmol) and 4-chloro-2-methoxy-6-methylaniline (200 mg, 1.17mmol) was stirred at 130° C. overnight. After cooling, the reactionmixture was neutralized by aqueous sodium hydrogen carbonate andextracted with ethyl acetate. The organics was dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residue waschromatographed on a silica gel column to give 68 mg (0.17 mmol, 44%) ofthe title compound.

¹H NMR (CDCl₃) δ 2.19 (3H, s), 3.74 (3H, s), 3.80 (3H, s), 3.95 (3H, s),6.17 (1H, br), 6.76 (1H, d, J=1.8 Hz), 6.88 (1H, d, J=1.8 Hz), 7.14 (1H,d, J=8.1 Hz), 7.53 (1H, d, J=8.1 Hz).

MS Calcd.: 393. Found: 394 (M+H).

1-{4-Chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl}-2,2-dimethylpropan-1-one

A n-pentane solution of tert-butyl lithium (1.46 M, 0.5 ml) was added toa solution of methyl4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazole-7-carboxylate(100 mg, 0.23 mmol) in diethyl ether (5 mL) at −78° C. and stirred for 1h. The reaction mixture was diluted with water (5 mL), stirred at roomtemperature for 0.5 h and extracted with ethyl acetate. The organics wasdried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by preparative HPLC. The resultant was neutralizedwith aqueous sodium hydrogen carbonate and extracted with ethyl acetate.The organics was dried over magnesium sulfate, filtered, andconcentrated in vacuo to give 31 mg (0.073, mmol, 32%) of the titlecompound.

mp. 249-250° C.

¹H NMR (CDCl₃) δ 1.37 (9H, s), 2.20 (3H, s), 3.37 (3H, s), 3.80 (3H, s),6.10 (1H, br), 6.78 (1H, d, J=1.8 Hz), 6.89 (1H, d, J=1.8 Hz), 7.08 (1H,d, J=8.1 Hz), 7.10 (1H, d, J=8.1 Hz).

MS Calcd.: 419. Found: 420 (M+H).

Example 1063-{4-Chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl}-2,2,4,4-tetramethylpentan-3-ol

A n-pentane solution of tert-butyl lithium (1.46 M, 0.5 ml) was added toa solution of methyl4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazole-7-carboxylate(100 mg, 0.23 mmol) in diethyl ether (5 ml) at −78° C. and stirred for 1h. The reaction mixture was diluted with water (5 mL), stirred at roomtemperature for 0.5 h and extracted with ethyl acetate. The organics wasdried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by preparative HPLC. The resultant was neutralizedwith aqueous sodium hydrogen carbonate and extracted with ethyl acetate.The organics were dried over magnesium sulfate, filtered, andconcentrated in vacuo to give 5 mg (0.010 mmol, 5%) of the titlecompound.

mp. 246-248° C.

¹H NMR (CDCl₃) δ 1.12 (18H, s), 2.20 (3H, s), 3.67 (3H, s), 3.75 (3H,s), 6.76 (1H, s), 6.87 (1H, s), 7.09 (1H, d, J=9.0 Hz), 7.21 (1H, d,J=9.0 Hz).

MS Calcd.: 477. Found: 478 (M+H).

Example 1073-{4-Chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl}-2,4-dimethylpentan-3-ol

To a solution of methyl4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazole-7-carboxylate(200 mg, 0.50 mmol) in diethylether (3 mL) was added dropwise a pentanesolution of isopropyl lithium (0.7 M solution, 5 mL) at −78° C., andstirred at 0° C. for 1 h. The reaction mixture was quenched with 6Nhydrochloric acid, and extracted with ethyl acetate. The organic layerwas dried over magnesium sulfate, filtered, and concentrated in vacuo.The residue was purified by preparative HPLC eluting with a 5-95%acetonitrile/water gradient mixture to give the title compound (153 mg,68%).

mp. 218-219° C.

¹H NMR (CDCl₃) δ 0.87 (d, J=6.9 Hz, 6H), 0.93 (d, J=6.9 Hz, 6H), 2.19(s, 3H), 2.31-2.43 (m, 2H), 3.77 (s, 3H), 3.87 (s, 3H), 6.76 (d, J=2.1Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 7.08 (d, J=8.4Hz, 1H).

MS Calcd.: 449. Found: 450 (M+H).

Example 1084-Chloro-N-(4-chloro-2-methoxy-6-methylphenyl)-7-(1-isopropyl-2-methylprop-1-en-1-yl)-1-methyl-1H-benzimidazol-2-amine

A solution of3-{4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl}-2,4-dimethylpentan-3-ol(75 mg, 0.17 mmol) in trifluoroacetic acid (3 mL) was heated at 70° C.for 1 h. After cooling, the reaction mixture was concentrated in vacuo,neutralized with saturated sodium hydrogen carbonate, and extracted withethyl acetate. The organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was purified bypreparative HPLC eluting with a 5-95% acetonitrile/water gradientmixture to give the title compound (58 mg, 80%).

mp. 166-168° C.

¹H NMR (CDCl₃) δ 0.65 (d, J=6.6 Hz, 3H), 1.06 (d, J=6.6 Hz, 3H), 1.40(s, 3H), 1.82 (s, 3H), 2.37 (s, 3H), 3.02-3.08 (m, 1H), 3.19 (s, 3H),3.67 (s, 3H), 6.70 (d, J=8.7 Hz, 1H), 6.76 (d, J=2.1 Hz, 1H), 6.90 (d,J=2.1 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H).

MS Calcd.: 431. Found: 432 (M+H).

Example 1094-Chloro-N-(4-chloro-2-methoxy-6-methylphenyl)-7-[(1Z)-1-ethylprop-1-en-1-yl]-1-methyl-1H-benzimidazol-2-amine

Example 109 was prepared in the similar method described in Example 108.

mp. 166-168° C.

¹H NMR (CDCl₃) δ 0.96 (t, J=7.5 Hz, 3H), 1.82 (d, J=6.6 Hz, 3H), 2.19(s, 3H), 2.32-2.57 (m, 2H), 3.58 (s, 3H), 3.80 (s, 3H), 5.52 (q, J=6.6Hz, 1H), 6.04 (s, 1H), 6.70 (d, J=8.1 Hz, 1H), 6.77 (d, J=2.1 Hz, 1H),6.88 (d, J=2.1 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H).

MS Calcd.: 403. Found: 404 (M+H).

Example 110-124 were prepared in the similar method described in Example77.

Example 1104-Chloro-N-(2,4-dichloro-6-methylphenyl)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp 237-238° C.

¹H NMR (CDCl₃) δ 0.85 (t, J=7.2 Hz, 6H), 1.60-1.85 (m, 4H), 2.18 (s,3H), 3.15-3.25 (m, 1H), 3.71 (s, 3H), 6.00-6.05 (m, 1H), 6.87 (d, J=8.4Hz, 1H), 7.05 (m, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H).

MS Calcd.: 409. Found: 410 (M+H), 412.

Example 1114-Chloro-N-(2,4-dimethoxy-6-methylpyridin-3-yl)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

¹H NMR (CDCl₃) δ 0.81 (t, J=7.5 Hz, 6H), 1.60-1.80 (m, 4H), 2.43 (s,3H), 3.15 (m, 1H), 3.66 (s, 3H), 3.78 (s, 3H), 3.88 (s, 3H), 6.45 (s,1H), 6.85 (d, J=8.1 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 7.25 (m, 1H).

MS Calcd.: 402. Found: 403 (M+H), 405.

Example 1124-Chloro-N-[2-methoxy-5-(trifluoromethyl)phenyl]-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amine

mp 178-180° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.80(m, 4H), 3.30-3.45 (m, 1H), 3.75 (s, 3H), 3.99 (s, 3H), 6.90-7.00 (m,3H), 7.20-7.30 (m, 2H), 8.24 (s, 1H).

MS Calcd.: 453. Found: 454 (M+H).

Example 1134-Chloro-N-[2,4-dichloro-5-(trifluoromethyl)phenyl]-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amine

mp 206-208° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.80(m, 4H), 3.30-3.45 (m, 1H), 3.86 (s, 3H), 6.89 (s, 1H), 7.00 (d, J=8.4Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 8.25-8.65 (br, 1H).

MS Calcd.: 493. Found: 494 (M+H).

Example 1144-Chloro-N-(4-chloro-2,6-dimethylphenyl)-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amine

mp 230-232° C.

¹H NMR (CDCl₃) δ 0.85 (t, J=7.5 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.80(m, 4H), 2.10-2.20 (m, 6H), 3.20-3.90 (m, 4H), 6.00 (s, 1H), 6.85 (d,J=8.4 Hz, 1H), 7.00-7.20 (m, 3H).

MS Calcd.: 417. Found: 418 (M+H).

Example 115N-(4-Bromo-2,6-dimethylphenyl)-4-chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amine

mp 234-236° C.

¹H NMR (CDCl₃) δ 0.85 (t, J=7.5 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.80(m, 4H), 2.10-2.20 (m, 6H), 3.15-3.80 (m, 4H), 5.90-6.20 (br, 1H), 6.85(d, J=8.4 Hz, 1H), 7.00-7.20 (m, 1H), 7.20-7.25 (m, 2H).

MS Calcd.: 463. Found: 464 (M+H).

Example 1165-{[4-Chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-yl]amino}-4-methylpyridin-2(1H)-one

mp 237-239° C.

¹H NMR (CDCl₃) δ 0.80-0.95 (m, 6H), 1.00-1.80 (m, 8H), 2.10-2.30 (m,3H), 3.20-4.85 (m, 4H), 5.55 (s, 1H), 6.30-7.70 (m, 4H), 8.35-8.60 (br,1H).

MS Calcd.: 386. Found: 387 (M+H).

Example 1174-Chloro-1-methyl-7-(1-propylbutyl)-N-(5,6,7,8-tetrahydronaphthalen-1-yl)-1H-benzimidazol-2-amine

mp 236-238° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.10-1.30 (m, 4H), 1.60-1.95(m, 8H), 2.66 (t, J=6.3 Hz, 2H), 2.81 (t, J=6.3 Hz, 2H), 3.20-3.40 (m,1H), 3.60 (s, 3H), 6.11 (s, 1H), 6.69 (d, J=7.8 Hz, 1H), 6.81 (d, J=7.8Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 7.03 (t, J=7.8 Hz, 1H), 7.20 (d, J=8.4Hz, 1H).

MS Calcd.: 409. Found: 410 (M+H).

Example 1184-Chloro-2-(5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-methyl-7-(1-propylbutyl)-1H-benzimidazole

¹H NMR (CDCl₃) δ 0.89 (t, J=7.5 Hz, 6H), 1.15-1.30 (m, 4H), 1.60-1.80(m, 4H), 3.17 (t, J=8.1 Hz, 2H), 3.30-3.50 (m, 1H), 3.76 (s, 6H), 4.20(t, J=8.1 Hz, 2H), 6.45-7.30 (m, 5H).

MS Calcd.: 411. Found: 412 (M+H).

Example 1191-[4-Chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-yl]-6-methoxy-1,2,3,4-tetrahydroquinoline

¹H NMR (CDCl₃) δ 0.86 (t, J=7.2 Hz, 6H), 1.15-1.30 (m, 4H), 1.55-1.75(m, 4H), 2.05-2.20 (m, 2H), 2.88 (t, J=6.6 Hz, 2H), 3.30-3.40 (m, 1H),3.58 (s, 3H), 3.75 (s, 3H), 3.88 (t, J=6.6 Hz, 2H), 6.34 (d, J=8.5 Hz,1H), 6.57 (dd, J=8.5, 3.0 Hz, 1H), 6.69 (d, J=3.0 Hz, 1H), 6.97 (d,J=8.1 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H).

MS Calcd.: 425. Found: 426 (M+H).

Example 1201-[4-Chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-yl]-7-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine

¹H NMR (CDCl₃) δ 0.80 (t, J=7.2 Hz, 6H), 1.05-1.20 (m, 4H), 1.50-1.90(m, 8H), 2.80-3.00 (m, 2H), 3.10-3.25 (m, 1H), 3.19 (s, 3H), 3.79 (s,3H), 3.80-4.30 (br, 2H), 6.95 (m, 2H), 6.79 (d, J=2.4 Hz, 1H), 6.87 (d,J=8.4 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H).

MS Calcd.: 439. Found: 440 (M+H).

Example 1215-Bromo-N-(4-chloro-2-methoxy-6-methylphenyl)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine

mp. 276-278° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 3H), 1.66-1.84 (m, 4H), 2.01 (s,3H), 2.14 (s, 3H), 3.13-3.21 (m, 1H), 3.82 (s, 3H), 3.83 (s, 3H),5.80-6.20 (br, 1H), 6.80 (d, J=2.4 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 7.05(s, 1H), 7.47 (s, 1H).

MS Calcd.: 493. Found: 494 (M+H).

Example 1225-Chloro-4-{[4-chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-yl]amino}-2-(trifluoromethyl)phenol

mp 197-199° C.

¹H NMR (CDCl₃) δ 0.87 (t, J=7.2 Hz, 6H), 1.15-1.35 (m, 4H), 1.60-1.80(m, 5H), 3.30-3.40 (m, 1H), 3.88 (s, 3H), 6.97 (d, J=8.4 Hz, 1H), 7.13(s, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.20-7.30 (m, 2H).

MS Calcd.: 473. Found: 474 (M+H).

Example 1234-Chloro-N-[2,4-dimethoxy-5-(trifluoromethyl)phenyl]-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amine

mp 196-198° C.

¹H NMR (CDCl₃) δ 0.85 (t, J=7.2 Hz, 6H), 1.15-1.30 (m, 4H), 1.60-1.80(m, 4H), 3.30-3.40 (m, 1H), 3.78 (s, 3H), 3.88 (s, 3H), 3.99 (s, 3H),6.57 (s, 1H), 6.66 (s, 1H), 6.92 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.4 Hz,1H), 8.22 (s, 1H).

MS Calcd.: 483. Found: 484 (M+H).

Example 124-144 were prepared in the similar method described in Example97.

Example 1244-Chloro-2-(mesityloxy)-1-methyl-7-(1-propylbutyl)-1H-benzimidazole

mp 165-167° C.

¹H NMR (CDCl₃) δ 0.88 (t, J=7.2 Hz, 6H), 1.20-1.40 (m, 4H), 1.60-1.80(m, 4H), 2.17 (s, 6H), 2.30 (s, 3H), 3.30-3.45 (m, 1H), 3.96 (s, 3H),6.85-6.95 (m, 3H), 7.10 (d, J=8.1 Hz, 1H).

MS Calcd.: 398. Found: 399 (M+H).

Example 1254-Chloro-2-(4-chloro-2,6-dimethylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

mp 168-169° C.

¹H NMR (CDCl₃) δ 0.87 (t, J=7.5 Hz, 6H), 1.60-1.85 (m, 4H), 2.81 (s,6H), 3.20-3.30 (m, 1H), 3.98 (s, 3H), 6.92 (d, J=8.1 Hz, 1H), 7.10 (s,2H), 7.13 (d, J=8.1 Hz, 1H).

MS Calcd.: 390. Found: 391 (M+H), 393.

Example 1264-Chloro-2-(2,6-dimethoxy-4-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

mp 161-162° C.

¹H NMR (CDCl₃) δ 0.84 (t, J=7.5 Hz, 6H), 1.60-1.85 (m, 4H), 2.36 (s,3H), 3.20-3.30 (m, 1H), 3.77 (s, 6H), 3.95 (s, 3H), 6.47 (s, 2H), 6.89(d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H).

MS Calcd.: 402. Found: 403 (M+H), 405.

Example 1274-Chloro-2-(2,4-dichlorophenoxy)-1-methyl-7-(1-propylbutyl)-1H-benzimidazole

mp 87-88° C.

¹H NMR (CDCl₃) δ 0.87 (t, J=7.2 Hz, 6H), 1.10-1.40 (m, 4H), 1.60-1.90(m, 4H), 3.30-3.45 (m, 1H), 3.97 (s, 3H), 6.98 (d, J=8.4 Hz, 1H), 7.17(d, J=8.4 Hz, 1H), 7.32 (dd, J=8.8, 2.4 Hz, 1H), 7.47 (d, J=2.4 Hz, 1H),7.74 (d, J=8.8 Hz, 1H).

MS Calcd.: 424. Found: 425 (M+H).

Example 1282-(4-Bromo-2-chlorophenoxy)-4-chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazole

mp 97-99° C.

¹H NMR (CDCl₃) δ 0.87 (t, J=7.2 Hz, 6H), 1.10-1.40 (m, 4H), 1.60-1.90(m, 4H), 3.30-3.45 (m, 1H), 3.97 (s, 3H), 6.98 (d, J=8.4 Hz, 1H), 7.18(d, J=8.4 Hz, 1H), 7.47 (dd, J=8.8, 2.4 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H),7.70 (d, J=8.8 Hz, 1H).

MS Calcd.: 470. Found: 471 (M+H).

Example 1294-Chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(1-propylbutyl)-1H-benzimidazole

mp 148-150° C.

¹H NMR (CDCl₃) δ 0.88 (t, J=7.2 Hz, 6H), 1.10-1.40 (m, 4H), 1.60-1.80(m, 4H), 2.31 (s, 3H), 3.30-3.45 (m, 1H), 3.98 (s, 3H), 6.95 (d, J=8.4Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.31 (d, J=2.4Hz, 1H).

MS Calcd.: 438. Found: 439 (M+H).

Example 1304-Chloro-2-(4-chloro-2,6-dimethylphenoxy)-1-methyl-7-(1-propylbutyl)-1H-benzimidazole

mp 160-162° C.

¹H NMR (CDCl₃) δ 0.88 (t, J=7.2 Hz, 6H), 1.15-1.40 (m, 4H), 1.60-1.80(m, 4H), 2.19 (s, 6H), 3.30-3.45 (m, 1H), 3.97 (s, 3H), 6.94 (d, J=8.4Hz, 1H), 7.10-7.20 (m, 3H).

MS Calcd.: 418. Found: 419 (M+H).

Example 1312-(4-Bromo-2,6-dimethylphenoxy)-4-chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazole

mp 155-157° C.

¹H NMR (CDCl₃) δ 0.88 (t, J=7.2 Hz, 6H), 1.20-1.40 (m, 0.4H), 1.60-1.80(m, 4H), 2.19 (s, 6H), 3.30-3.45 (m, 1H), 3.97 (s, 3H), 6.94 (d, J=8.4Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.20-7.30 (m, 2H).

MS Calcd.: 464. Found: 465 (M+H).

Example 1324-Chloro-1-methyl-7-(1-propylbutyl)-2-(2,4,6-trichlorophenoxy)-1H-benzimidazole

mp 148-150° C.

¹H NMR (CDCl₃) δ 0.88 (t, J=7.2 Hz, 6H), 1.20-1.40 (m, 4H), 1.60-1.80(m, 4H), 3.30-3.45 (m, 1H), 3.99 (s, 3H), 6.97 (d, J=8.4 Hz, 1H), 7.15(d, J=8.4 Hz, 1H), 7.26 (s, 1H), 7.43 (s, 1H).

MS Calcd.: 458. Found: 459 (M+H).

Example 1334-Chloro-2-(2,6-dimethoxy-4-methylphenoxy)-1-methyl-7-(1-propylbutyl)-1H-benzimidazole

mp 203-205° C.

¹H NMR (CDCl₃) δ 0.87 (t, J=7.2 Hz, 6H), 1.15-1.40 (m, 4H), 1.60-1.80(m, 4H), 2.36 (s, 3H), 3.30-3.45 (m, 1H), 3.77 (s, 6H), 3.95 (s, 3H),6.47 (s, 2H), 6.90 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H).

MS Calcd.: 430. Found: 431 (M+H).

Example 1349-{[4-Chloro-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-yl]oxy}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one

mp 150-152° C.

¹H NMR (CDCl₃) δ 0.88 (t, J=7.2 Hz, 6H), 1.15-1.40 (m, 4H), 1.60-1.80(m, 4H), 2.70 (t, J=7.8 Hz, 2H), 2.98 (t, J=7.8 Hz, 2H), 3.17 (t, J=8.7Hz, 2H), 3.30-3.45 (m, 1H), 3.92 (s, 3H), 4.10 (t, J=8.7 Hz, 2H),6.90-7.05 (m, 3H), 7.17 (d, J=8.1 Hz, 1H).

MS Calcd.: 451. Found: 452 (M+H).

Example 1352-(2-Bromo-4-chlorophenoxy)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

mp 114-115° C.

¹H NMR (CDCl₃) δ 0.85 (t, J=7.2 Hz, 6H), 1.60-1.85 (m, 4H), 3.15-3.30(m, 1H), 3.98 (s, 3H), 6.96 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H),7.37 (dd, J=2.4, 8.7 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.76 (d, J=7.8 Hz,1H)

MS Calcd.: 440. Found: 441 (M+H), 443, 445.

Example 1365-Bromo-2-(4-chloro-2,6-dimethylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

mp 214-216° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.65-1.83 (m, 4H), 2.18 (s,6H), 3.18-3.26 (m, 1H), 3.95 (s, 3H), 7.08-7.10 (m, 3H), 7.46 (d, J=2.1Hz, 1H).

MS Calcd.: 433. Found: 434 (M+H).

Example 1372-(4-Bromo-2,6-dimethylphenoxy)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

mp 197-198° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.2 Hz, 6H), 1.75-1.82 (m, 4H), 2.18 (s,6H), 3.19-3.25 (m, 1H), 3.97 (s, 3H), 6.91 (d, J=8.1 Hz, 1H), 7.12 (d,J=8.1 Hz, 1H), 7.24 (s, 2H).

MS Calcd.: 434. Found: 435 (M+H).

Example 1384-Chloro-7-(1-ethylpropyl)-1-methyl-2-(2,4,6-trichlorophenoxy)-1H-benzimidazole

mp 155-157° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.2 Hz, 6H), 1.65-1.77 (m, 4H), 3.18-3.25(m, 1H), 3.99 (s, 3H), 6.93 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H),7.42 (s, 2H).

MS Calcd.: 430. Found: 431 (M+H).

Example 1394-Chloro-7-(1-ethylpropyl)-2-[(4-methoxy-2,6-dimethylpyridin-3-yl)oxy]-1-methyl-1H-benzimidazole

mp 183-184° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.2 Hz, 6H), 1.68-1.82 (m, 4H), 2.45 (s,3H), 2.52 (s, 3H), 3.20-3.26 (m, 1H), 3.76 (s, 3H), 3.96 (s, 3H), 6.66(s, 1H), 6.91 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H).

MS Calcd.: 387. Found: 388 (M+H).

Example 1404-Chloro-2-[2,6-dichloro-4-(trifluoromethoxy)phenoxy]-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

mp 145-147° C.

¹H NMR (CDCl₃) δ 0.85 (t, J=7.2 Hz, 6H), 1.68-1.82 (m, 4H), 3.20-3.24(m, 1H), 4.00 (s, 3H), 6.95 (d, J=8.4 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H),7.32 (s, 2H).

MS Calcd.: 480. Found: 481 (M+H).

Example 1413-{[4-Chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-yl]oxy}-N,N,2,6-tetramethylpyridin-4-amine

mp 175-177° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.2 Hz, 6H), 1.70-1.82 (m, 4H), 2.27 (s,3H), 2.46 (s, 3H), 2.92 (s, 6H), 3.20-3.24 (m, 1H), 3.97 (s, 3H), 6.49(s, 1H), 6.91 (d, J=8.1 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H).

MS Calcd.: 400. Found: 401 (M+H).

Example 1423,5-Dichloro-4-{[4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-yl]oxy}-N,N-dimethylaniline

mp 200-202° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.2 Hz, 6H), 1.68-1.81 (m, 4H), 2.97 (s,6H), 3.20-3.26 (m, 1H), 3.98 (s, 3H), 6.62 (s, 2H), 6.91 (d, J=8.4 Hz,1H), 7.12 (d, J=8.4 Hz, 1H).

MS Calcd.: 439. Found: 440 (M+H).

Example 1433,5-Dichloro-2-{[4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-yl]oxy}-N,N-dimethylbenzamide

mp 141-143° C.

¹H NMR (CDCl₃) δ 0.84 (t, J=7.2 Hz, 6H), 1.67-1.81 (m, 4H), 2.63 (s,3H), 3.08 (s, 3H), 3.20-3.23 (m, 1H), 3.95 (s, 3H), 6.95 (d, J=8.4 Hz,1H), 7.14 (d, J=8.4 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.51 (d, J=2.4 Hz,1H).

MS Calcd.: 467. Found: 468 (M+H).

Example 1444-Chloro-2-(4-chloro-2-methoxy-6-methylphenoxy)-7-(1-ethyl-1-propyl)-1-methyl-1H-benzimidazole

mp 165-167° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.2 Hz, 6H), 1.75-1.82 (m, 4H), 2.27 (s,3H), 3.20-3.24 (m, 1H), 3.71 (s, 3H), 3.95 (s, 3H), 6.81 (d, J=2.4 Hz,1H), 6.86 (d, J=2.4 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 7.11 (d, J=8.1 Hz,1H).

MS Calcd.: 406. Found: 407 (M+H).

Example 1452-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole

A mixture of 2,4-dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole(200 mg, 0.750 mmol), 2,4-dichloro-6-methylphenol (398 mg, 2.25 mmol),potassium carbonate (311 mg, 2.25 mmol) and 1-methyl-2-pyrrolidone (0.5ml) was stirred at 120° C. for 12 h under nitrogen atmosphere. Themixture was diluted with water, extracted with ethyl acetate, and washedwith brine. The organic layer was dried over magnesium sulfate, andconcentrated in vacuo. The residue was purified by chromatography onsilica gel with a 2-30% ethyl acetate/n-hexane gradient mixture andcrystallized from methanol to afford the title compound as colorlesscrystals (109 mg, 36%).

mp 130-131° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.60-1.85 (m, 4H), 2.30 (s,3H), 3.15-3.25 (m, 1H), 3.89 (s, 3H), 3.97 (s, 3H), 6.64 (d, J=8.4 Hz,1H), 6.92 (d, J=8.4 Hz, 1H), 7.15 (d, J=1.8 Hz, 1H), 7.25 (d, J=1.8 Hz,1H).

MS Calcd.: 406. Found: 407 (M+H), 409.

Example 1462-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole

Example 146 was prepared in the similar method described in Example 145.

mp 106-107° C.

¹H NMR (CDCl₃) δ 0.85 (t, J=7.2 Hz, 6H), 1.50-1.85 (m, 4H), 3.10-3.25(m, 1H), 3.92 (s, 3H), 3.97 (s, 3H), 6.66 (d, J=8.7 Hz, 1H), 6.95 (d,J=8.7 Hz, 1H), 7.32 (dd, J=2.4, 7.8 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H),7.66 (d, J=7.8 Hz, 1H)

MS Calcd.: 436. Found: 437 (M+H), 439, 441.

Example 1472-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-4-ol

To a solution of2-(2-bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole(80 mg, 0.18 mmol) in dichloromethane (2 mL) was added dropwise adichloromethane solution (1M, 2 mL) of boron tribromide at 0° C., andstirred at room temperature for 1 h. The reaction mixture was cooled at0° C., quenched with water, and extracted with ethyl acetate. Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was washed with isopropyl ether andhexane (1:1) to give the title compound (67 mg, 86%).

mp 175-177° C.

¹H NMR (CDCl₃) δ 0.85 (t, J=7.5 Hz, 6H), 1.66-1.82 (m, 4H), 3.08-3.18(m, 1H), 3.96 (s, 3H), 6.00-6.40 (br, 1H), 6.71 (d, J=8.1 Hz, 1H), 6.92(d, J=8.1 Hz, 1H), 7.35 (dd, J=2.4, 8.7 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H),7.65 (d, J=2.4 Hz, 1H).

MS Calcd.: 422. Found: 423 (M+H).

Example 1482-(2-Bromo-4-chlorophenoxy)-4-(difluoromethoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole

To a solution of aqueous potassium hydroxide (50% solution) was addeddropwise a solution of2-(2-bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-4-olin dichloromethane (2 mL) at 0° C. After stirring for 20 min, to thereaction mixture was bubbled chlorodifluoromethane at 0° C. for 30 min.The reaction mixture was diluted with water, and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, filtered,and concentrated in vacuo. The residue was purified by preparative HPLCeluting with a 5-95% acetonitrile/water gradient mixture to give thetitle compound as an oil (24 mg, 43%).

¹H NMR (CDCl₃) δ 0.85 (t, J=7.2 Hz, 6H), 1.64-1.87 (m, 4H), 3.17-3.27(m, 1H), 3.99 (s, 3H), 6.94-7.00 (m, 2H), 7.09 (t, J=76 Hz, 1H), 7.38(dd, J=2.4, 8.7 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H).

MS Calcd.: 472. Found: 473 (M+H).

Example 1492-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-4-(2-furyl)-1-methyl-1H-benzimidazole

7-(1-Ethylpropyl)-4-(2-furyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-one

To a mixture of4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-one(150 mg, 0.505 mmol) and 2-(tributhylstanyl)furan (361 mg, 1.01 mmol) intoluene (2 ml) was added tetrakis(triphenylphosphine)palladium(0) (117mg, 0.101 mmol) and the mixture was refluxed for 3 h. After cooling, thesolvent was evaporated in vacuo and the residue was diluted with ethylacetate. The ethyl acetate solution was washed with aqueous saturatedsodium bicarbonate and brine, dried over magnesium sulfate filtered andconcentrated under vacuum. The residue was purified by preparative HPLCeluting with a 5-95% acetonitrile/water gradient mixture to give 81 mg(0.285 mmol, 56%) of the title compound.

¹H NMR (CDCl₃) δ 0.83 (t, J=7.5 Hz, 6H), 1.60-1.80 (m, 4H), 3.10-3.25(m, 1H), 3.66 (s, 3H), 6.52 (dd, J=2.1, 3.3 Hz, 1H), 6.68 (d, J=3.3 Hz,1H), 6.95 (d, J=8.1 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.51 (d, J=2.1 Hz,1H), 8.74 (s, 1H).

MS Calcd.: 284. Found: 285 (M+H).

2-Chloro-7-(1-ethylpropyl)-4-(2-furyl)-1-methyl-1H-benzimidazole

A mixture of7-(1-ethylpropyl)-4-(2-furyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-one(79 mg, 0.278 mmol) in phosphorous oxychloride (0.78 ml, 8.33 mmol) wasstirred at 120° C. for 2 h. The reaction was allowed to cool to roomtemperature and concentrated in vacuo. The residue was dissolved inethyl acetate, washed with aqueous saturated sodium bicarbonate andbrine. The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel with a 1-30% ethyl acetate/n-hexane gradient mixture to give44 mg (0.145 mmol, 52%) of the title compound.

¹H NMR (CDCl₃) δ 0.82 (t, J=7.5 Hz, 6H), 1.65-1.85 (m, 4H), 3.20-3.35(m, 1H), 4.01 (s, 3H), 6.54 (dd, J=1.8, 3.3 Hz, 1H), 7.15 (d, J=7.8 Hz,1H), 7.40-7.50 (m, 2H), 7.67 (d, J=7.8 Hz, 1H).

MS Calcd.: 302. Found: 303 (M+H), 305.

2-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-4-(2-furyl)-1-methyl-1H-benzimidazole

A mixture of2-chloro-7-(1-ethylpropyl)-4-(2-furyl)-1-methyl-1H-benzimidazole (42 mg,0.139 mmol), 2-bromo-4-chlorophenol (87 mg, 0.417 mmol) and potassiumcarbonate (58 mg, 0.417 mmol) was heated at 120° C. for 18 h under anargon atmosphere. The mixture was diluted with water. The aqueoussolution was extracted with ethyl acetate. The extract was washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by column chromatography on silica gel with a1-20% ethyl acetate/n-hexane gradient mixture to give 45 mg (0.0950mmol, 68%) of the title compound) as a colorless crystal.

mp 159-162° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.70-1.85 (m, 4H), 3.20-3.35(m, 1H), 4.01 (s, 3H), 6.47 (dd, J=1.5, 3.3 Hz, 1H), 7.09 (d, J=8.1 Hz,1H), 7.20 (d, J=3.3 Hz, 1H), 7.35-7.45 (m, 2H), 7.64 (d, J=8.1 Hz, 1H),7.66 (s, 1H), 7.85 (d, J=9.0 Hz, 1H).

MS Calcd.: 472. Found: 473 (M+H), 475.

Example 1502-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile

7-(1-Ethylpropyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carbonitrile

A mixture of4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one(300 mg, 1.01 mmol) and copper cyanide (116 mg, 1.30 mmol) in1-methyl-2-pyrrolidone (3 mL) was irradiated by microwave (200 w) at150° C. for 1 h. After cooling, to the reaction mixture was diluted withsaturated sodium bicarbonate, and extracted with ethyl acetate. Theextract was dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was washed with 50% diisopropyl ether/n-hexane togive the title compound (209 mg, 86%).

¹H NMR (CDCl₃) δ 0.81 (t, J=7.8 Hz, 6H), 1.57-1.83 (m, 4H), 3.18-3.27(m, 1H), 3.67 (s, 3H), 6.98 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H),9.51 (s, 1H).

MS Calcd.: 243. Found: 244 (M+H).

2-Chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile

A mixture of7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (3.80 g,15.6 mmol) and phosphorus oxychloride (50 mL) was heated at 120° C. for6 h. After cooling, the reaction mixture was poured into a crushed iceand stirred for 30 min, neutralized with sodium hydrogen carbonate andextracted with ethyl acetate. The organic layers were dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue waswashed with diisopropyl ether to give the title compound (3.76 g, 92%).

¹H NMR (CDCl₃) δ 0.83 (t, J=7.5 Hz, 6H), 1.65-1.91 (m, 4H), 3.27-3.36(m, 1H), 4.05 (s, 3H), 7.18 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H).

MS Calcd.: 261. Found: 262 (M+H).

2-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile

A mixture of2-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile (250mg, 0.957 mmol), 2-bromo-4-chlorophenol (595 mg, 2.87 mmol), potassiumcarbonate (397 mg, 2.87 mmol) and 1-methyl-2-pyrrolidone (0.5 ml) wasstirred at 120° C. for 12 h under nitrogen atmosphere. The mixture wasdiluted with water, extracted with ethyl acetate, and washed with brine.The organic layer was dried over magnesium sulfate, and concentrated invacuo. The residue was purified by chromatography on silica gel with a2-30% ethyl acetate/n-hexane gradient mixture and crystallized frommethanol to afford the title compound as colorless crystals (134 mg,32%).

mp 136-137° C.

¹H NMR (CDCl₃) δ 0.85 (t, J=7.5 Hz, 6H), 1.65-1.90 (m, 4H), 3.25-3.35(m, 1H), 4.02 (s, 3H), 7.07 (d, J=8.1 Hz, 1H), 7.39 (dd, J=2.4, 8.7 Hz,1H), 7.47 (d, J=8.1 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.81 (d, J=7.8 Hz,1H)

MS Calcd.: 431. Found: 432 (M+H), 434.

Example 1512-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile

Example 151 was prepared in the similar method described in Example 150.

mp 192-192° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.2 Hz, 6H), 1.65-1.90 (m, 4H), 2.31 (s,3H), 3.20-3.35 (m, 1H), 4.01 (s, 3H), 7.04 (d, J=8.4 Hz, 1H), 7.22 (d,J=2.4 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H).

MS Calcd.: 401. Found: 402 (M+H), 404.

Example 1522-[(4-Chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile

A mixture of2-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile(1.00 g, 3.82 mmol), 4-chloro-2-methoxy-6-methylaniline (1.97 g, 11.50mmol) and 1-methyl-2-pyrrolidone (0.5 ml) was heated at 130° C. for 48h. After cooling, the reaction mixture was diluted with aqueoussaturated sodium hydrogen carbonate. The mixture was extracted withethyl acetate, dried over magnesium sulfate and concentrated in vacuo.The residue was purified by column chromatography on silica gel to givethe title compound as a white powder (670 mg, 44%).

¹H NMR (CDCl₃) δ 0.83 (t, J=7.5 Hz, 6H), 1.64-1.85 (m, 4H), 2.20 (s,3H), 3.17-3.27 (m, 1H), 3.79 (s, 6H), 6.13 (s, 1H), 6.78 (d, J=2.1 Hz,1H), 6.89 (d, J=2.1 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.37 (d, J=8.1 Hz,1H). MS Calcd.: 396. Found: 397 (M+H). mp. 223-225° C.

Example 153 Methyl2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carboxylate

Methyl7-(1-ethylpropyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate

A mixture of7-(1-ethylpropyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carbonitrile(1.50 g, 6.17 mmol), potassium hydroxide (20.0 g, 356 mmol), water (30ml) and ethanol (30 ml) was heated under reflux for 48 h. The reactionmixture was concentrated in vacuo. The residue was diluted with ethylacetate and 2N hydrochloric acid was added and extracted. The extractswere washed with water, dried over magnesium sulfate and concentrated invacuo to give crude carboxylic acid. Trimethyl orthoacetate (10 ml) andtoluene (10 ml) were added to the residue and heated at 100° C. for 6 h.The reaction mixture was concentrated in vacuo. The residue was purifiedby column chromatography on silica gel with a 35% ethyl acetate/n-hexaneto give 1.31 g (4.74 mmol, 77%) of the title compound as a white powder.

¹H NMR (CDCl₃) δ 0.81 (t, J=7.44 Hz, 6H), 1.57-1.88 (m, 4H), 3.15-3.31(m, 1H), 3.65 (s, 3H), 3.95 (s, 3H), 6.96 (d, J=8.48 Hz, 1H), 7.62 (d,J=8.67 Hz, 1H), 9.21 (s, 1H).

MS: Calcd.: 276. Found: 277 (M+H).

Methyl2-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carboxylate

A mixture of methyl7-(1-ethylpropyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate(1.30 g, 4.70 mmol) and phosphoryl chloride (10 ml) was heated at 100°C. for 3 h. The mixture was diluted with toluene and concentrated invacuo to remove excess reagent. The residue was diluted with aqueoussaturated sodium bicarbonate and extracted with ethyl acetate. Theextracts were washed with water, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by chromatography oncolumn silica gel with a 10% ethyl acetate/n-hexane to give 1.18 g (4.00mmol, 85%) of the title compound as a colorless oil.

¹H NMR (CDCl₃) δ 0.82 (t, J=7.35 Hz, 6H), 1.64-1.91 (m, 4H), 3.27-3.40(m, 1H), 4.01 (s, 3H), 4.05 (s, 3H), 7.19 (d, J=8.10 Hz, 1H), 7.92 (d,J=8.29 Hz, 1H).

Methyl2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carboxylate

A mixture of methyl2-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carboxylate (1.15g, 3.90 mmol), 4,6-dichloro-o-cresol (2.07 g, 11.70 mmol), potassiumcarbonate (2.16 g, 15.60 mmol) and N,N-dimethylformamide (15 ml) washeated at 110° C. for 5 h. The residue was diluted with aqueoussaturated sodium bicarbonate and extracted with ethyl acetate. Theextracts were washed with water, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon alumina with a 15% ethyl acetate/n-hexane to give 1.41 g (3.24 mmol,83%) of the title compound as a white powder.

mp 177-178° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.44 Hz, 6H), 1.65-1.92 (m, 4H), 2.36 (s,3H), 3.25-3.39 (m, 1H), 3.84 (s, 3H), 4.03 (s, 3H) 7.06 (d, J=8.29 Hz,1H), 7.21 (d, J=1.88 Hz, 1H), 7.30 (d, J=2.64 Hz, 1H), 7.79 (d, J=8.29Hz, 1H).

MS: Calcd.: 435. Found: 436 (M+H).

Example 154[2-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-4-yl]methanol

A mixture of methyl2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carboxylate(1.00 g, 2.30 mmol), lithium borohydride (100 mg, 4.60 mmol) andtetrahydrofuran (20 ml) was heated at 55° C. for 1 h. The reactionmixture was concentrated in vacuo. The residue was diluted with aqueoussaturated sodium bicarbonate and extracted with ethyl acetate. Theextracts were washed with water, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel with a 30% ethyl acetate/n-hexane to give 920 mg (2.26mmol, 98%) of the title compound as a white powder.

mp 141-143° C.

¹H NMR (CDCl₃) δ 0.87 (t, J=7.35 Hz, 6H), 1.66-1.88 (m, 4H), 2.29 (s,3H), 3.16-3.30 (m, 1H), 3.90 (d, J=6.31 Hz, 1H), 3.99 (s, 3H), 4.85 (d,J=6.22 Hz, 2H), 6.98 (s, 2H), 7.20 (d, J=1.70 Hz, 1H), 7.32 (d, J=2.45Hz, 1H).

MS: Calcd.: 407. Found: 408 (M+H).

Example 1552-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbaldehyde

A mixture of[2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-4-yl]methanol(100 mg, 0.25 mmol), manganese(IV) oxide (428 mg, 4.92 mmol) andtetrahydrofuran (5 ml) was stirred at room temperature for 16 h. Thereaction mixture was concentrated in vacuo. The residue was purified bycolumn chromatography on alumina with a 50% ethyl acetate/n-hexane togive 93 mg (0.23 mmol, 93%) of the title compound as a white powder.

mp 148-149° C.

¹H NMR (CDCl₃) δ 0.87 (t, J=7.44 Hz, 6H), 1.70-1.93 (m, 4H), 2.32 (s,3H), 3.25-3.39 (m, 1H), 4.04 (s, 3H), 7.11 (d, J=8.29 Hz, 1H), 7.24 (d,J=1.88 Hz, 1H), 7.35 (d, J=2.45 Hz, 1H), 7.72 (d, J=8.10 Hz, 1H), 10.55(s, 1H).

Example 1562-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-4-(pyrrolidin-1-ylmethyl)-1H-benzimidazole

To a mixture of2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbaldehyde(93 mg, 0.23 mmol), pyrrolidine (33 mg, 0.46 mmol), acetic acid (0.5 ml)and ethyl acetate (1.5 ml) was added sodium triacetoxyborohydride (244mg, 1.15 mmol) and the reaction mixture was stirred at room temperaturefor 1 h. The residue was diluted with aqueous saturated sodiumbicarbonate and extracted with ethyl acetate. The extracts were washedwith water, dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography on alumina with a 5% ethylacetate/n-hexane to give 100 mg (0.22 mmol, 94%) of the title compoundas a white powder.

mp 107-108° C.

¹H NMR (CDCl₃) δ 0.87 (t, J=7.35 Hz, 6H), 1.65-1.86 (m, 8H), 2.30 (s,3H), 2.47-2.59 (m, 4H), 3.20-3.26 (m, 1H), 3.83 (s, 2H), 3.97 (s, 3H),6.98 (d, J=7.91 Hz, 1H), 7.17 (d, J=7.91 Hz, 1H), 7.21 (d, J=1.88 Hz,1H), 7.32 (d, J=2.45 Hz, 1H).

MS: Calcd.: 460. Found: 461 (M+H).

Example 157N-{[2-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-4-yl]methyl}-N-methylethanamine

To a mixture of2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbaldehyde(120 mg, 0.296 mmol), methyl amine (2M tetrahydrofuran solution, 1.48ml, 2.96 mmol), acetic acid (0.5 ml) and ethyl acetate (2.0 ml) wasadded sodium triacetoxyborohydride (314 mg, 1.48 mmol) and the reactionmixture was stirred at room temperature for 48 h. The residue wasdiluted with aqueous saturated sodium bicarbonate and extracted withethyl acetate. The extracts were washed with water, dried over magnesiumsulfate and concentrated in vacuo. The residue was purified bychromatography on alumina with a 5% ethyl acetate/n-hexane to give 93 mg(0.21 mmol, 70%) of the title compound as a white powder.

¹H NMR (CDCl₃) δ 0.87 (t, J=7.35 Hz, 6H), 1.04 (t, J=7.16 Hz, 3H),1.65-1.87 (m, 4H), 2.18 (s, 3H), 2.29 (s, 3H), 2.42 (q, J=7.16 Hz, 2H),3.16-3.31 (m, 1H), 3.72 (s, 2H), 3.97 (s, 3H), 6.98 (d, J=7.91 Hz, 1H),7.14 (d, J=7.91 Hz, 1H), 7.18-7.23 (m, 1H), 7.31 (d, J=1.88 Hz, 1H).

MS: Calcd.: 448. Found: 449 (M+H).

Example 158N-(4-Chloro-2-methoxy-6-methylphenyl)-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazol-2-amine

Methyl 2-nitro-4-(trifluoromethyl)benzoate

A mixture of 2-nitro-4-trifluoromethylbenzoic acid (23.5 g, 0.10 mol),trimethyl orthoacetate (60.1 g, 0.50 mol) and toluene (60 ml) was heatedat 80° C. for 16 h. The reaction mixture was concentrated in vacuo.Toluene was added and concentrated again to remove excess reagent. Theresidue was purified by column chromatography on silica gel with a 1-10%ethyl acetate/n-hexane gradient mixture to give 24.9 g (0.50 mol 100%)of the title compound as a colorless oil.

¹H NMR (CDCl₃) δ: 3.97 (s, 3H), 7.87-7.90 (m, 1H), 7.95-7.97 (m, 1H),8.22 (s, 1H).

Methyl 2-amino-4-(trifluoromethyl)benzoate

A mixture of methyl 2-nitro-4-(trifluoromethyl)benzoate (2.49 g 0.01mol), sodium hydrosulfite (8.71 g, 0.05 mol), ethanol (20 ml) and water(20 ml) was heated at 50° C. for 3 h. Water was added and extracted withethyl acetate. The extracts were washed with water, dried over magnesiumsulfate and concentrated in vacuo. The residue was purified by columnchromatography on silica gel with a 5% ethyl acetate/n-hexane to give1.46 g (6.67 mmol 67%) of the title compound as a white powder.

¹H NMR (CDCl₃) δ 3.90 (s, 3H), 5.50-6.20 (brs, 2H), 6.85 (d, J=8.48 Hz,1H), 6.90 (s, 1H), 7.95 (d, J=8.48 Hz, 1H).

MS Calcd.: 219. Found: 220 (M+H).

Methyl 2-(acetylamino)-4-(trifluoromethyl)benzoate

A mixture of methyl 2-amino-4-(trifluoromethyl)benzoate (8.00 g, 0.036mol), acetic anhydride (11.18 g, 0.109 mol), pyridine (8.62 g, 0.109mol) and chloroform (20 ml) was stirred at room temperature for 48 h.The reaction mixture was concentrated in vacuo. The residue was dilutedwith water and extracted with ethyl acetate. The extracts were washedwith 1N hydrochloric acid and water, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel with a 50% ethyl acetate/n-hexane to give 8.10 g (0.031mol 86%) of the title compound as a white powder.

mp 86-87° C.

¹H NMR (CDCl₃) δ 2.26 (s, 3H), 3.97 (s, 3H), 7.32 (dd, J=1.41, 8.38 Hz,1H), 8.14 (d, J=8.29 Hz, 1H), 9.08 (s, 1H), 11.11 (s, 1H).

MS Calcd.: 261. Found: 262 (M+H).

Methyl 2-(acetylamino)-3-nitro-4-(trifluoromethyl)benzoate

To an ice-cooled nitric acid (fuming) (20 ml) was added methyl2-(acetylamino)-4-(trifluoromethyl)benzoate (7.30 g, 0.028 mol)portionwise and stirred for 30 min. The reaction mixture was poured intoice-water and extracted with ethyl acetate. The extracts were washedwith aqueous saturated sodium bicarbonate and water, dried overmagnesium sulfate and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel with a 30% ethyl acetate/n-hexane togive 3.20 g (0.010 mol, 38%) of the title compound as a yellow powder.

¹H NMR (CDCl₃) δ 2.21 (s, 3H), 3.98 (s, 3H), 7.68 (d, J=8.29 Hz, 1H),8.19 (d, J=8.29 Hz, 1H), 9.10 (s, 1H).

Methyl 2-amino-3-nitro-4-(trifluoromethyl)benzoate

A mixture of methyl 2-(acetylamino)-3-nitro-4-(trifluoromethyl)benzoate(1.00 g, 3.27 mmol) and 10% hydrochloric acid in methanol solution (10ml) was heated at 55° C. for 16 h. The reaction mixture was concentratedin vacuo. The residue was diluted with aqueous saturated sodiumbicarbonate and extracted with ethyl acetate. The extracts were washedwith water, dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel with a 30%ethyl acetate/n-hexane to give 780 mg (0.030 mol 90%) of the titlecompound as a yellow powder.

¹H NMR (CDCl₃) δ3.95 (s, 3H), 6.90-7.15 (brs, 2H), 6.99 (d, J=8.29 Hz,1H), 8.16 (d, J=8.29 Hz, 1H).

Methyl 2,3-diamino-4-(trifluoromethyl)benzoate

To a stirring solution of methyl2-amino-3-nitro-4-(trifluoromethyl)benzoate (5.80 g, 0.022 mol),ammonium formate (30.0 g, 0.476 mol) in ethanol (300 ml) was added 10%palladium on carbon (500 mg) at room temperature and stirred for 2 h.Insoluble was filtered off and filtrates were concentrated in vacuo. Theresidue was diluted with water and extracted with ethyl acetate. Theextracts were washed with water, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel with a 20% ethyl acetate/n-hexane to give 5.10 g (0.022mol, 99%) of the title compound as a yellow powder.

¹H NMR (CDCl₃) δ 3.87 (brs, 2H), 3.90 (s, 3H), 5.68 (brs, 2H), 6.88 (d,J=8.67 Hz, 1H), 7.47 (d, J=8.67 Hz, 1H).

MS Calcd.: 234. Found: 235 (M+H).

Methyl2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-4-carboxylate

To a stirring solution of methyl 2,3-diamino-4-(trifluoromethyl)benzoate(5.10 g, 0.022 mol) and diisopropylethylamine (6.26 g, 0.048 mol) intoluene (50 ml) was added a solution of triphosgene (2.58 g, 0.0087 mol)in toluene (20 ml) dropwise and stirred at room temperature for 16 h.The reaction mixture was concentrated in vacuo. The residue was dilutedwith 1N hydrochloric acid and extracted with ethyl acetate andtetrahydrofuran. The extracts were washed with water, dried overmagnesium sulfate and concentrated in vacuo. A solution of 50%diisopropylether/n-hexane was added to the residue and whiteprecipitates were filtered, washed with same solvent to give 5.00 g(0.019 mol 87%) of the title as a white powder

mp. 281-283° C.

¹H NMR (DMSO-d₆) δ 3.92 (s, 3H) 7.32 (d, J=8.48 Hz, 1H), 7.61 (d, J=8.48Hz, 1H), 11.23 (s, 1H), 11.63 (s, 1H).

MS Calcd.: 260. Found: 261 (M+H)

Methyl3-methyl-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-4-carboxylate

To a stirring mixture of methyl2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-4-carboxylate(2.34 g, 9.00 mmol), di-t-butyl dicarbonate (4.32 g, 20.0 mmol) andN,N-dimethylformamide (240 ml) was added 60% sodium hydride (800 mg,20.0 mmol) portionwise and stirred at 50° C. for 2 h. The reactionmixture was poured into 1N hydrochloric acid and extracted with ethylacetate. The extracts were washed with aqueous saturated sodiumbicarbonate and water, dried over magnesium sulfate and concentrated invacuo. A solution of 50% diisopropylether/n-hexane was added to theresidue and white precipitates (starting materials) were filtered off.The filtrates were concentrated in vacuo to give crude 1-tert-butyl4-methyl2-oxo-7-(trifluoro-methyl)-2,3-dihydro-1H-benzimidazole-1,4-dicarboxylateas a colorless oil.

To a stirring mixture of obtained crude dicarboxylate, methyl iodide(2.82 g, 20.0 mmol) and N,N-dimethylformamide (10 ml) was added 60%sodium hydride (800 mg, 20.0 mmol) portionwise and stirred at roomtemperature for 30 min. The reaction mixture was poured into 1Nhydrochloric acid and extracted with ethyl acetate. The extracts werewashed with aqueous saturated sodium bicarbonate and water, dried overmagnesium sulfate and concentrated in vacuo to give crude 1-tert-butyl4-methyl3-methyl-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-1,4-dicarboxylateas a colorless oil.

A mixture of obtained crude 1,4-dicarboxylate and trifluoroacetic acid(5 ml) was stirred at 50° C. for 10 min and concentrated in vacuo. Theresidue was diluted with aqueous saturated sodium bicarbonate andextracted with ethyl acetate. The extracts were washed with water, driedover magnesium sulfate and concentrated in vacuo. The residue waspurified by column chromatography on silica gel with a 20% ethylacetate/n-hexane to give 1.13 g (4.12 mmol 46%) of the title compound asa white powder.

¹H NMR (CDCl₃) δ 3.57 (s, 3H), 3.99 (s, 3H), 7.29 (d, J=8.48 Hz, 1H),7.54 (dd, J=0.75, 8.48 Hz, 1H), 9.36 (brs, 1H).

MS Calcd.: 274. Found: 275 (M+H).

7-(1-Ethylprop-1-en-1-yl)-1-methyl-4-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one

To an ice-cooled solution of, methyl3-methyl-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-4-carboxylate(2.80 g, 10.2 mmol) in tetrahydrofuran (30 ml) was added a solution of3M ethylmagnesium bromide in diethylether (13.6 ml, 40.8 mmol) dropwiseand stirred at 45° C. for 16 h. Methanol and water were carefully addedto decompose excess reagent. 2N hydrochloric acid was added andextracted with ethyl acetate. The extracts were washed with aqueoussaturated sodium bicarbonate and water, dried over magnesium sulfate andconcentrated in vacuo. Ethanol (40 ml) and conc. hydrochloric acid (10ml) were added to the residue and the resulting mixture was heated at80° C. for 6 h. The reaction mixture was concentrated in vacuo. Aqueoussaturated sodium bicarbonate was added to the residue and extracted withethyl acetate. The extracts were washed with water, dried over magnesiumsulfate and concentrated in vacuo. The residue was purified bychromatography on silica gel with a 20% ethyl acetate/n-hexane to give609 mg (2.14 mmol, 21%, cis/trans=3/1) of the title compound as a whitepowder.

¹H NMR (CDCl₃) δ 0.97 (t, J=7.50 Hz, 3H×0.75), 1.06 (t, J=7.44 Hz,3H×0.25), 1.39-1.45 (m, 3H×0.25), 1.83 (d, J=6.78 Hz, 3H×0.75),2.19-2.68 (m, 2H), 3.44 (s, 3H), 5.49 (q, J=6.78 Hz, 1H×0.75), 5.74 (q,J=6.78 Hz, 1H×0.25), 6.80 (d, J=8.10 Hz, 1H×0.25), 6.86 (d, J=8.10 Hz,1H×0.75), 7.19 (d, J=8.29 Hz, 1H×0.75), 7.24 (d, J=8.28 Hz, 1H×0.25),9.07 (s, 1H).

MS Calcd.: 284. Found: 285 (M+H).

7-(1-Ethylpropyl)-1-methyl-4-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one

A mixture of7-(1-ethylprop-1-en-1-yl)-1-methyl-4-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one(486 mg, 1.71 mmol), 10% palladium on carbon (200 mg) and acetic acid (5ml) was hydrogenated under 5 atom of hydrogen at 50° C. for 2 h.Catalyst was filtered off and filtrates were concentrated in vacuo.Aqueous saturated sodium bicarbonate was added to the residue andextracted with ethyl acetate. The extracts were washed with water, driedover magnesium sulfate and concentrated in vacuo. The residue waspurified by recrystallization from diisopropylether/n-hexane to give 350mg (1.22 mmol, 72%) of the title compound as a white powder.

mp. 205-206° C.

¹H NMR (CDCl₃) δ 0.82 (t, J=7.44 Hz, 6H), 1.58-1.88 (m, 4H), 3.14-3.36(m, 1H), 3.67 (s, 3H), 7.02 (d, J=8.48 Hz, 1H), 7.21-7.27 (m, 1H), 8.92(brs, 1H).

MS Calcd.: 286. Found: 287 (M+H).

2-Chloro-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole

A mixture of7-(1-ethylpropyl)-1-methyl-4-(trifluoro-methyl)-1,3-dihydro-2H-benzimidazol-2-one(310 mg, 1.08 mmol) and phosphoryl chloride (5 ml) was heated at 110° C.for 1 h and concentrated in vacuo. Toluene was added and concentratedagain to remove excess reagent. Aqueous saturated sodium bicarbonate wasadded to the residue and extracted with ethyl acetate. The extracts werewashed with water, dried over magnesium sulfate and concentrated invacuo. The residue was purified by column chromatography on silica gelwith a 20% ethyl acetate/n-hexane to give 300 mg (0.99 mmol, 91%) of thetitle compound as a colorless oil.

¹H NMR (CDCl₃) δ 0.83 (t, J=7.50 Hz, 6H), 1.65-1.91 (m, 4H), 3.24-3.40(m, 1H), 4.05 (s, 3H), 7.19 (d, J=7.91 Hz, 1H), 7.53 (d, J=8.10 Hz, 1H).

MS Calcd.: 304. Found: 305 (M+H).

N-(4-Chloro-2-methoxy-6-methylphenyl)-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazol-2-amine

A mixture of2-chloro-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole(290 mg, 0.95 mmol), 4-chloro-2-methoxy-6-methylaniline (491 mg, 2.86mmol) and N-methyl-2-pyrrolidinone (3 drops) was heated at 110° C. for72 h. Aqueous saturated sodium bicarbonate was added to the residue andextracted with ethyl acetate. The extracts were washed with water, driedover magnesium sulfate and concentrated in vacuo. The residue waspurified by chromatography on silica gel with a 10% ethylacetate/n-hexane and recrystallized from diisopropylether/n-hexane togive 140 mg (0.32 mmol, 34%) of the title compound as a white powder.

mp. 187-188° C.

¹H NMR (CDCl₃) δ 0.83 (t, J=7.35 Hz, 6H), 1.63-1.89 (m, 4H), 2.18 (s,3H), 3.20-3.30 (m, 1H), 3.74 (s, 3H), 3.78 (s, 3H), 6.18 (s, 1H), 6.78(s, 1H), 6.88 (d, J=2.07 Hz, 1H), 6.97 (d, J=8.29 Hz, 1H), 7.36 (d,J=8.29 Hz, 1H).

MS Calcd.: 440. Found: 441 (M+H).

Example 159N-(2-Bromo-4-chlorophenyl)-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazol-2-amine

Example 159 was prepared in the similar method described in Example 158.

mp. 151-152° C.

¹H NMR (CDCl₃) δ 0.84 (t, J=7.44 Hz, 6H), 1.65-1.91 (m, 4H), 3.19-3.34(m, 1H), 3.87 (s, 3H), 6.93 (s, 1H), 7.07 (d, J=8.10 Hz, 1H), 7.34 (dd,J=2.45, 8.85 Hz, 1H), 7.45 (d, J=7.35 Hz, 1H), 7.56 (d, J=2.45 Hz, 1H),8.29 (d, J=8.67 Hz, 1H).

MS Calcd.: 474. Found: 475 (M+H).

Example 1602-(2,4-Dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole

A mixture of2-chloro-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole(304 mg, 1.00 mmol), 4,6-dichloro-o-cresol (531 mg, 3.00 mmol),potassium carbonate (553 mg, 4.0 mmol) and N,N-dimethylformamide (5 ml)was heated at 110° C. for 48 h. Aqueous saturated sodium bicarbonate wasadded to the residue and extracted with ethyl acetate. The extracts werewashed with water, dried over magnesium sulfate and concentrated invacuo. The residue was purified by column chromatography on silica gelwith a 10% ethyl acetate/n-hexane and recrystallization fromdiisopropylether/n-hexane to give 290 mg (0.65 mmol, 65%) of the titlecompound as a white powder.

mp. 149-151° C.

¹H NMR (CDCl₃) δ 0.87 (t, J=7.35 Hz, 6H), 1.66-1.91 (m, 4H), 2.31 (s,3H), 3.24-3.37 (m, 1H), 4.02 (s, 3H), 7.05 (d, J=8.10 Hz, 1H), 7.21 (d,J=1.88 Hz, 1H), 7.31 (d, J=2.45 Hz, 1H), 7.39 (d, J=8.10 Hz, 1H).

MS Calcd.: 445. Found: 446 (M+H).

Example 1612-(2-Bromo-4-chlorophenoxy)-7-(1-ethylpropyl)-1-methyl-4-(trifluoromethyl)-1H-benzimidazole

Example 161 was prepared in the similar method described in Example 160.

mp. 119-120° C.

¹H NMR (CDCl₃) δ 0.85 (t, J=7.44 Hz, 6H), 1.65-1.91 (m, 4H), 3.24-3.37(m, 1H), 4.02 (s, 3H), 7.10 (d, J=8.10 Hz, 1H), 7.39 (dd, J=2.45, 8.85Hz, 1H), 7.44 (d, J=8.29 Hz, 1H), 7.64 (d, J=2.45 Hz, 1H), 7.95 (d,J=9.04 Hz, 1H).

MS Calcd.: 475. Found: 476 (M+H).

Example 1622-(2,4-Dichloro-6-methylphenoxy)-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazole

A suspension of2-chloro-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazole (92mg, 0.318 mmol), 2,4-dichloro-6-methylphenol (114 mg, 0.643 mmol),potassium carbonate (89 mg, 0.643 mmol) in N,N-dimethylformamide (1.5ml) was stirred at 90° C. for 5.5 days (2,4-dichloro-6-methylphenol andpotassium carbonate were added in three equal portions each over 5.5days). After cooling, the reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel eluting witha 10-25% ethyl acetate/n-hexane gradient mixture to give 107 mg (0.249mmol, 78.3%) of the title compound as an oil. The oil was crystallizedfrom hexane to give 70 mg (51%) as a pale yellow crystal.

mp: 115-119° C.

¹H NMR (CDCl₃) δ: 1.19 (3H, t, J=7.5 Hz), 1.32 (3H, t, J=7.5 Hz), 2.26(3H, s), 2.50 (2H, q, J=7.5 Hz), 2.72 (2H, q, J=7.5 Hz), 3.23 (3H, s),6.10 (1H, s), 7.09-7.19 (3H, m), 7.31 (1H, d, J=2.4 Hz), 7.57 (1H, d,J=6.9 Hz).

MS Calcd.: 428. Found: 429 (M+H), 431.

Example 1633,5-Dichloro-4-{([7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazol-2-yl]oxy}-N,N-dimethylaniline

Example 163 was prepared in the similar method described in Example 145.

mp 176-177° C.

¹H NMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.65-1.85 (m, 4H), 2.94 (s,6H), 3.15-3.25 (m, 1H), 3.89 (s, 3H), 3.97 (s, 3H), 6.63 (d, J=8.4 Hz,1H), 6.63 (s, 2H), 6.91 (d, J=8.4 Hz, 1H).

MS Calcd.: 435. Found: 436 (M+H), 438.

Experiment 1 Measurement of Corticotropin-Releasing Factor (CRF) BindingInhibitory Rate

A receptor binding experiment was carried out using a human CRF receptorexpressing CHO cellular membrane fraction and ovine CRF, [¹²⁵I]-tyr⁰(¹²⁵I-CRF). 1000 nM of a test compound was incubated with 1 μg of humanCRF receptor expressing CHO cellular membrane fraction and 50 pM of¹²⁵I-CRF in a binding assay buffer (50 mM Tris-HCl, 5 mM EDTA, 10 mMMgCl₂, 0.05% CHAPS, 0.1% BSA, 0.5 mM PMSF, 0.1 μg/ml pepstatin, 20 μg/mlleupeptin, pH 7.5). In addition, for measuring nonspecific binding(NSB), 0.1 μM unlabelled human Urocortin was incubated with 1 μg ofhuman CRF receptor expressing CHO cellular membrane fraction and 50 pMof ¹²⁵I-CRF in a binding assay buffer. After a binding reaction wascarried out at room temperature for 1.5 hour, the membrane was entrappedon a glass filter (UniFilter plate GF-C/Perkin Elmer) by suctionfiltration using a cell harvester (Perkin Elmer), and washed withice-cooled 50 mM Tris-HCl (pH 7.5). After drying the glass filter, aliquid scintillation cocktail (Microscinti 0, Perkin Elmer) was added,and the radioactivity of ¹²⁵I-CRF remaining on a glass filter wasmeasured using Topcount (Perkin Elmer).

(TB−SB)/(TB−NSB)×100 (SB: radioactivity when a compound is added, TB:maximum binding radioactivity, NSB: nonspecific binding radioactivity)was calculated to obtain a binding inhibitory rate under the presence of1,000 nM of each test substances. The IC₅₀ values were calculated byusing GraphPad Prism software.

Binding inhibitory rates of respective compounds measured by theaforementioned method are shown in Table 8.

TABLE 8 Binding inhibitory Example rate (%) No. 1000 nM 1 >80 9 >8064 >80 69 >80 77 >80 84 >80 90 >80 97 >80 101 >80 103 >80

Values of IC₅₀ of respective compounds were measured by theaforementioned method, and are shown as A and B in Table 9. [A: lessthan 10 nM; B: 10-50 nM]

TABLE 9 Example No. IC₅₀ (nM) 15 B 66 B 77 B 97 A 101 A 145 A

INDUSTRIAL APPLICABILITY

Compound (I) or (I′) of the present invention has an excellent CRFantagonistic activity, and therefore useful as drugs for treating orpreventing affective disorder, depression, anxiety, and the like.

1. A compound represented by formula (I):

wherein R¹ is an acyclic branched C₃₋₇ alkyl optionally substituted withhydroxyl; a phenyl optionally substituted with a halogen, nitro,hydroxyl, C₁₋₆ alkoxy, amino, methyl, methylaminomethyl, ethyl orpropyl; or a N-linked pyrrolyl or pyrazolyl each of which may besubstituted with 1 to 3 substituents selected from the group consistingof C₁₋₆ alkyl and C₆₋₁₀ aryl; R² is a phenyl which may be substitutedwith acetyl, propionyl, dimethylaminocarbonyl, methylaminocarbonyl,dimethylamino, methylamino, amino, halogen, methyl, ethyl,trifluoromethyl, methoxy, ethoxy or trifluoromethoxy; X is —NR³—(wherein R³ is a C₁₋₈ alkyl optionally substituted with hydroxyl); Y¹ isCR^(3a), wherein R^(3a) is a hydrogen, a halogen, a cyano, a C₁₋₃ alkyloptionally substituted with hydroxyl, or a C₁₋₃ alkoxy optionallysubstituted with halogen; Y² is CR^(3b), wherein R^(3b) is a hydrogen;Y³ is CR^(3c), wherein R^(3c) is a hydrogen; and Z is an oxygen or—NR⁴—, wherein R⁴ is a hydrogen; or a salt thereof.
 2. The compoundaccording to claim 1, wherein R¹ is an acyclic branched C₃₋₇ alkyloptionally substituted with hydroxyl.
 3. The compound according to claim1, wherein R¹ is a phenyl optionally substituted with a halogen, nitro,hydroxyl, C₁₋₆ alkoxy, amino, methyl, methylaminomethyl, ethyl orpropyl.
 4. The compound according to claim 1, wherein R¹ is a N-linkedpyrrolyl or pyrazolyl each of which may be substituted with 1 to 3substituents selected from the group consisting of C₁₋₆ alkyl and C₆₋₁₀aryl.
 5. The compound according to claim 1, wherein R³ is methyl, ethylor hydroxyethyl.
 6. The compound according to claim 1, wherein R^(3a) ishydrogen, chlorine, bromine, methoxy or methyl.
 7. The compoundaccording to claim 1, wherein R² is phenyl which is2,4,6-trisubstituted, 2,4,5-trisubstituted or 2,4-disubstituted.
 8. Thecompound according to claim 1 which isN-(4-chloro-2-methoxy-6-methylphenyl)-7-(2-ethylphenyl)-1-methyl-1H-benzimidazol-2-amine,N-(4-bromo-2-methoxy-6-methylphenyl)-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazol-2-amine,N-(4-bromo-2-methoxy-6-methylphenyl)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine,N-(4-chloro-2-methoxy-6-methylphenyl)-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazol-2-amine,or4-chloro-N-(2,4-dichloro-6-methylphenyl)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amine,or a salt thereof.
 9. A pharmaceutical composition which comprises thecompound according to claim
 1. 10. A CRF receptor antagonist which isthe compound represented by the formula (I):

according to claim 1; or a salt thereof.
 11. A method for treatingaffective disorder, depression, anxiety or irritable bowel syndrome,which comprises administering to a subject in need thereof an effectiveamount of the CRF receptor antagonist according to claim
 10. 12. Apharmaceutical composition for treating affective disorder, depression,anxiety or irritable bowel syndrome, which comprises the CRF receptorantagonist according to claim
 10. 13. The compound according to claim 1which is4-chloro-2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole,or2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazole,or a salt thereof. 14.N-(4-chloro-2-methoxy-6-methylphenyl)-7-(2-ethylphenyl)-1-methyl-1H-benzimidazol-2-amineor a salt thereof. 15.N-(4-bromo-2-methoxy-6-methylphenyl)-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazol-2-amineor a salt thereof. 16.N-(4-bromo-2-methoxy-6-methylphenyl)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amineor a salt thereof. 17.N-(4-chloro-2-methoxy-6-methylphenyl)-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazol-2-amineor a salt thereof. 18.4-chloro-N-(2,4-dichloro-6-methylphenyl)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-2-amineor a salt thereof. 19.4-chloro-2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazoleor a salt thereof. 20.2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-4-methoxy-1-methyl-1H-benzimidazoleor a salt thereof.